VENLAFAXINE HYDROCHLORIDE - venlafaxine hydrochloride capsule,extended release ACETRIS HEALTH, LLC----------

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VENLAFAXINEHYDROCHLORIDE EXTENDED-RELEASE CAPSULES safely and effectively. See full prescribinginformation for VENLAFAXINE HYDROCHLORIDE EXTENDED-RELEASE CAPSULES.

VENLAFAXINE HYDROCHLORIDE extended-release capsules, for oral useInitial U.S. Approval: 1997

WARNING: SUICIDAL THOUGHTS AND BEHAVIORSSee full prescribing information for complete boxed warning.

• Increased risk of suicidal thinking and behavior in children, adolescents and youngadults taking antidepressants (5.1) • Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1) • Venlafaxine hydrochloride extended-release capsules are not approved for use inpediatric patients (8.4)

RECENT MAJOR CHANGESDosage and Administration, Discontinuing Venlafaxine HydrochlorideExtended-Release Capsules (2.8) 11/2021Warnings and Precautions, Discontinuation Syndrome (5.7) 11/2021Warnings and Precautions, Sexual Dysfunction (5.13) 9/2021

INDICATIONS AND USAGEVenlafaxine hydrochloride extended-release capsules are a serotonin and norepinephrine reuptakeinhibitor (SNRI) indicated for the treatment of:

Major Depressive Disorder (MDD)Generalized Anxiety Disorder (GAD)Social Anxiety Disorder (SAD)Panic Disorder (PD)

DOSAGE AND ADMINISTRATION

Indication Starting Dose Target Dose Maximum Dose MDD (2.1) 37.5 to 75 mg/day 75 mg/day 225 mg/dayGAD (2.2) 37.5 to 75 mg/day 75 mg/day 225 mg/daySAD (2.3) 75 mg/day 75 mg/day 75 mg/dayPD (2.4) 37.5 mg/day 75 mg/day 225 mg/day

Take once daily with food (2). Capsules should be taken whole; do not divide, crush, chew, or dissolve(2).When discontinuing treatment, reduce the dose gradually (2.8, 5.7).Renal impairment: reduce the total daily dose by 25% to 50% in patients with renal impairment. Reducethe total daily dose by 50% or more in patients undergoing dialysis or with severe renal impairment(2.6).Hepatic impairment: reduce the daily dose by 50% in patients with mild to moderate hepaticimpairment. In patients with severe hepatic impairment or hepatic cirrhosis, it may be necessary toreduce the dose by more than 50% (2.6).

DOSAGE FORMS AND STRENGTHSVenlafaxine hydrochloride extended-release capsules USP are available as 37.5 mg, 75 mg and 150 mg

Venlafaxine hydrochloride extended-release capsules USP are available as 37.5 mg, 75 mg and 150 mgstrengths (3).Each capsule contains venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg or 150 mg ofvenlafaxine (3).

CONTRAINDICATIONSHypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in thevenlafaxine hydrochloride extended-release capsules formulation (4.1).Do not use with an MAOI or within 14 days of stopping an MAOI. Allow 7 days after stopping venlafaxinehydrochloride extended-release capsules before starting an MAOI, because of the risk of serotoninsyndrome (4.2, 5.2, 7.3).

WARNINGS AND PRECAUTIONSClinical Worsening/Suicide Risk: Monitor for clinical worsening and suicide risk (5.1).Serotonin Syndrome: Risk increases with concomitant use of other serotonergic drugs. Discontinuevenlafaxine hydrochloride extended-release capsules and initiate supportive treatment if serotoninsyndrome occurs (4.2, 5.2, 7.3).Elevations in Blood Pressure: Control hypertension before initiating treatment. Monitor bloodpressure regularly during treatment (5.3).Abnormal Bleeding: Venlafaxine hydrochloride extended-release capsules may increase risk ofbleeding events. Caution patients about the risk of bleeding associated with the concomitant use ofvenlafaxine hydrochloride extended-release capsules and NSAIDs, aspirin, or other drugs that affectcoagulation (5.4).Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreatedanatomically narrow angles treated with antidepressants (5.5).Activation of Mania/Hypomania: Use cautiously in patients with bipolar disorder. Caution patientsabout the risk of activation of mania/hypomania (5.6).Sexual Dysfunction: venlafaxine hydrochloride extended-release capsules may cause symptoms ofsexual dysfunction (5.13).

ADVERSE REACTIONSMost common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea,somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, erectile dysfunction, andlibido decreased (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Acetris Health, LLC at 1-833-395-6929or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONSSerotonergic Drugs (e.g., MAOIs, triptans, SSRIs, other SNRIs, linezolid, lithium,tramadol, or St. John’s wort): Potential for serotonin syndrome. Careful patient observation isadvised (4.2, 5.2, 7.3).

USE IN SPECIFIC POPULATIONSPregnancy: Based on animal data, may cause fetal harm (8.1).Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother(8.3)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.Revised: 1/2022

FULL PRESCRIBING INFORMATION: CONTENTS*WARNING: SUICIDAL THOUGHTS AND BEHAVIORS1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder1.2 Generalized Anxiety Disorder1.3 Social Anxiety Disorder

1.4 Panic Disorder2 DOSAGE AND ADMINISTRATION

2.1 Major Depressive Disorder2.2 Generalized Anxiety Disorder2.3 Social Anxiety Disorder (Social Phobia)2.4 Panic Disorder2.5 Switching Patients from Venlafaxine Hydrochloride Tablets2.6 Specific Populations2.7 Maintenance Treatment2.8 Discontinuing Venlafaxine Hydrochloride Extended-Release Capsules2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended toTreat Psychiatric Disorders

3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS

4.1 Hypersensitivity4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs)

5 WARNINGS AND PRECAUTIONS5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults5.2 Serotonin Syndrome5.3 Elevations in Blood Pressure5.4 Abnormal Bleeding5.5 Angle-Closure Glaucoma5.6 Activation of Mania/Hypomania5.7 Discontinuation Syndrome5.8 Seizures5.9 Hyponatremia5.10 Weight and Height Changes in Pediatric Patients5.11 Appetite Changes in Pediatric Patients5.12 Interstitial Lung Disease and Eosinophilic Pneumonia5.13 Sexual Dysfunction

6 ADVERSE REACTIONS6.1 Clinical Studies Experience6.2 Vital Sign Changes6.3 Laboratory Changes6.4 Pediatric Patients6.5 Adverse Reactions Identified During Postapproval Use

7 DRUG INTERACTIONS7.1 Central Nervous System (CNS)-Active Drugs7.2 Monoamine Oxidase Inhibitors7.3 Serotonergic Drugs7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)7.5 Weight Loss Agents7.6 Effects of Other Drugs on Venlafaxine Hydrochloride Extended-Release Capsules7.7 Effects of Venlafaxine Hydrochloride Extended-Release Capsules on Other Drugs7.8 Drug-Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Labor and Delivery8.3 Nursing Mothers8.4 Pediatric Use

8.5 Geriatric Use8.6 Age and Gender8.7 Use in Patient Subgroups

9 DRUG ABUSE AND DEPENDENCE9.1 Controlled Substance9.2 Abuse9.3 Dependence

10 OVERDOSAGE10.1 Human Experience10.2 Management of Overdosage

11 DESCRIPTION12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES14.1 Major Depressive Disorder14.2 Generalized Anxiety Disorder14.3 Social Anxiety Disorder (also known as Social Phobia)14.4 Panic Disorder14.5 Pediatric Patients

16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*

FULL PRESCRIBING INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORSAntidepressants increased the risk of suicidal thoughts and behavior inchildren, adolescents, and young adults in short-term studies. Thesestudies did not show an increase in the risk of suicidal thoughts andbehavior with antidepressant use in patients over age 24; there was areduction in risk with antidepressant use in patients aged 65 and older[see Warnings and Precautions (5.1)].

In patients of all ages who are started on antidepressant therapymonitor closely for clinical worsening and emergence of suicidalthoughts and behaviors. Advise families and caregivers of the need forclose observation and communication with the prescriber [see Warningsand Precautions (5.1) and Patient Counseling Information (17)].

Venlafaxine hydrochloride extended-release capsules are not approvedfor use in pediatric patients [see Use in Specific Populations (8.4)].

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

1.1 Major Depressive DisorderVenlafaxine hydrochloride extended-release capsules are indicated for the treatment ofmajor depressive disorder (MDD). Efficacy was established in three short-term (4, 8, and12 weeks) and two long-term, maintenance trials.

1.2 Generalized Anxiety DisorderVenlafaxine hydrochloride extended-release capsules are indicated for the treatment ofGeneralized Anxiety Disorder (GAD). Efficacy was established in two 8-week and two 26-week placebo-controlled trials.

1.3 Social Anxiety DisorderVenlafaxine hydrochloride extended-release capsules are indicated for the treatment ofSocial Anxiety Disorder (SAD), also known as social phobia. Efficacy was established infour 12-week and one 26-week, placebo-controlled trials.

1.4 Panic DisorderVenlafaxine hydrochloride extended-release capsules are indicated for the treatment ofPanic Disorder (PD), with or without agoraphobia. Efficacy was established in two 12-week placebo-controlled trials.

2 DOSAGE AND ADMINISTRATIONVenlafaxine hydrochloride extended-release capsules should be administered in a singledose with food, either in the morning or in the evening at approximately the same timeeach day [see Clinical Pharmacology (12.3)]. Each capsule should be swallowed wholewith fluid and not divided, crushed, chewed, or placed in water or it may be administeredby carefully opening the capsule and sprinkling the entire contents on a spoonful ofapplesauce. This drug/food mixture should be swallowed immediately without chewingand followed with a glass of water to ensure complete swallowing of the pellets(spheroids).

2.1 Major Depressive DisorderFor most patients, the recommended starting dose for venlafaxine hydrochlorideextended-release capsules are 75 mg per day, administered in a single dose. For somepatients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow newpatients to adjust to the medication before increasing to 75 mg per day. Patients notresponding to the initial 75 mg per day dose may benefit from dose increases to amaximum of 225 mg per day. Dose increases should be in increments of up to 75 mgper day, as needed, and should be made at intervals of not less than 4 days, sincesteady-state plasma levels of venlafaxine and its major metabolites are achieved in mostpatients by day 4 [see Clinical Pharmacology (12.3)]. In the clinical studies establishingefficacy, upward titration was permitted at intervals of 2 weeks or more.

It should be noted that, while the maximum recommended dose for moderatelydepressed outpatients is also 225 mg per day for venlafaxine hydrochloride (immediate-release), more severely depressed inpatients in one study of the development programfor that product responded to a mean dose of 350 mg per day (range of 150 to 375 mgper day). Whether or not higher doses of venlafaxine hydrochloride extended-releasecapsules are needed for more severely depressed patients is unknown; however, theexperience with venlafaxine hydrochloride extended-release capsules doses higher than225 mg per day is very limited.

2.2 Generalized Anxiety DisorderFor most patients, the recommended starting dose for venlafaxine hydrochlorideextended-release capsules is 75 mg per day, administered in a single dose. For somepatients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow newpatients to adjust to the medication before increasing to 75 mg per day. Patients notresponding to the initial 75 mg per day dose may benefit from dose increases to amaximum of 225 mg per day. Dose increases should be in increments of up to 75 mgper day, as needed, and should be made at intervals of not less than 4 days, sincesteady-state plasma levels of venlafaxine and its major metabolites are achieved in mostpatients by day 4 [see Clinical Pharmacology (12.3)].

2.3 Social Anxiety Disorder (Social Phobia)The recommended dose is 75 mg per day, administered in a single dose. There was noevidence that higher doses confer any additional benefit.

2.4 Panic DisorderThe recommended starting dose is 37.5 mg per day of venlafaxine hydrochlorideextended-release capsules for 7 days. Patients not responding to 75 mg per day maybenefit from dose increases to a maximum of approximately 225 mg per day. Doseincreases should be in increments of up to 75 mg per day, as needed, and should bemade at intervals of not less than 7 days.

2.5 Switching Patients from Venlafaxine Hydrochloride TabletsDepressed patients who are currently being treated at a therapeutic dose withvenlafaxine hydrochloride (immediate release) may be switched to venlafaxinehydrochloride extended-release capsules at the nearest equivalent dose (mg per day),e.g., 37.5 mg venlafaxine twice a day to 75 mg venlafaxine hydrochloride extended-release capsules once daily. However, individual dosage adjustments may be necessary.

2.6 Specific PopulationsPatients with Hepatic Impairment

The total daily dose should be reduced by 50% in patients with mild (Child-Pugh=5 to 6)to moderate (Child-Pugh=7 to 9) hepatic impairment. In patients with severe hepaticimpairment (Child-Pugh=10 to 15) or hepatic cirrhosis, it may be necessary to reducethe dose by 50% or more [see Use in Specific Populations (8.7)].

Patients with Renal Impairment

The total daily dose should be reduced by 25% to 50% in patients with mild (CLcr= 60 to89 mL/min) or moderate (CLcr= 30 to 59 mL/min) renal impairment. In patientsundergoing hemodialysis or with severe renal impairment (CLcr < 30 mL/min), the totaldaily dose should be reduced by 50% or more. Because there was much individualvariability in clearance between patients with renal impairment, individualization of dosagemay be desirable in some patients [see Use in Specific Populations (8.7)].

2.7 Maintenance TreatmentThere is no body of evidence available from controlled studies to indicate how longpatients with MDD, GAD, SAD, or PD should be treated with venlafaxine hydrochlorideextended-release capsules.

It is generally agreed that acute episodes of MDD require several months or longer ofsustained pharmacological therapy beyond response to the acute episode. Venlafaxinehydrochloride extended-release capsules/venlafaxine hydrochloride have demonstratedcontinuation of response in clinical studies up to 52 weeks, at the same dose at whichpatients responded during the initial treatment [see Clinical Studies (14.1)]. It is notknown whether or not the dose of venlafaxine hydrochloride extended-release capsulesneeded for maintenance treatment is identical to the dose needed to achieve an initialresponse. Patients should be periodically reassessed to determine the need formaintenance treatment and the appropriate dose for such treatment.

In patients with GAD and SAD, venlafaxine hydrochloride extended-release capsuleshave been shown to be effective in 6-month clinical studies. The need for continuingmedication in patients with GAD and SAD who improve with venlafaxine hydrochlorideextended-release capsules treatment should be periodically reassessed.

In a clinical study for PD, patients continuing venlafaxine hydrochloride extended-releasecapsules at the same dose at which they responded during the initial 12 weeks oftreatment experienced a statistically significantly longer time to relapse than patientsrandomized to placebo [see Clinical Studies (14.4)]. The need for continuing medicationin patients with PD who improve with venlafaxine hydrochloride extended-releasecapsules treatment should be periodically reassessed.

2.8 Discontinuing Venlafaxine Hydrochloride Extended-Release CapsulesA gradual reduction in the dose, rather than abrupt cessation, is recommended whendiscontinuing therapy with venlafaxine hydrochloride extended-release capsules. Inclinical studies with venlafaxine hydrochloride extended-release capsules, tapering wasachieved by reducing the daily dose by 75 mg at one-week intervals. Individualization oftapering may be necessary [see Warnings and Precautions (5.7)]. In some patients,discontinuation may need to occur over a period of several months.

2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI)Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI (intended to treatpsychiatric disorders) and initiation of therapy with venlafaxine hydrochloride extended-release capsules. In addition, at least 7 days should be allowed after stoppingvenlafaxine hydrochloride extended-release capsules before starting an MAOI intendedto treat psychiatric disorders [see Contraindications (4.2), Warnings and Precautions(5.2), and Drug Interactions (7.2)].

Use of Venlafaxine Hydrochloride Extended-Release Capsules with otherMAOIs such as Linezolid or Intravenous Methylene Blue

Do not start venlafaxine hydrochloride extended-release capsules in a patient who isbeing treated with linezolid or intravenous methylene blue, because there is an increasedrisk of serotonin syndrome. In a patient who requires more urgent treatment of apsychiatric condition, other interventions, including hospitalization should be considered[see Contraindications (4.2)].

In some cases, a patient already receiving venlafaxine hydrochloride extended-releasecapsules therapy may require urgent treatment with linezolid or intravenous methyleneblue. If acceptable alternatives to linezolid or intravenous methylene blue are notavailable and the potential benefits of linezolid or intravenous methylene blue treatmentare judged to outweigh the risks of serotonin syndrome in a particular patient,venlafaxine hydrochloride extended-release capsules should be stopped promptly, andlinezolid or intravenous methylene blue can be administered. Monitor the patient forsymptoms of serotonin syndrome for 7 days or until 24 hours after the last dose oflinezolid or intravenous methylene blue, whichever comes first. Therapy with venlafaxinehydrochloride extended-release capsules can be resumed 24 hours after the last doseof linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].

The risk of administering methylene blue by non-intravenous routes (such as oral tabletsor by local injection) or in intravenous doses much lower than 1 mg/kg concomitantlywith venlafaxine hydrochloride extended-release capsules are unclear. The clinicianshould, nevertheless, be aware of the possibility of emergent symptoms of serotoninsyndrome with such use [see Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHSVenlafaxine hydrochloride extended-release capsules USP are available in the followingstrengths:

37.5 mg capsules are white to off white spherical to oval pellets filled in empty hardgelatin capsule shell (size ‘3’) of opaque grey color cap and opaque peach color bodyimprinted with “E” on cap and “73” on the body with edible black ink.75 mg capsules are white to off white spherical to oval pellets filled in empty hardgelatin capsule shell (size ‘1’) of opaque peach color cap and opaque peach colorbody imprinted with “E” on cap and “74” on the body with edible black ink.150 mg capsules are white to off white spherical to oval pellets filled in empty hardgelatin capsule shell (size ‘0’) of opaque dark orange color cap and opaque dark

orange color body imprinted with “E” on cap and “89” on the body with edible blackink.

4 CONTRAINDICATIONS

4.1 HypersensitivityHypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to anyexcipients in the formulation

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs)The use of MAOIs (intended to treat psychiatric disorders) concomitantly withvenlafaxine hydrochloride extended-release capsules or within 7 days of discontinuingtreatment with venlafaxine hydrochloride extended-release capsules are contraindicatedbecause of an increased risk of serotonin syndrome. The use of venlafaxinehydrochloride extended-release capsules within 14 days of discontinuing treatment withan MAOI (intended to treat psychiatric disorders) is also contraindicated [see Dosageand Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)].

Starting venlafaxine hydrochloride extended-release capsules in a patient who is beingtreated with an MAOI such as linezolid or intravenous methylene blue is alsocontraindicated, because of an increased risk of serotonin syndrome [see Dosage andAdministration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and YoungAdultsPatients with major depressive disorder (MDD), both adult and pediatric, may experienceworsening of their depression and/or the emergence of suicidal ideation and behavior(suicidality) or unusual changes in behavior, whether or not they are takingantidepressant medications, and this risk may persist until significant remission occurs.Suicide is a known risk of depression and certain other psychiatric disorders, and thesedisorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worseningof depression and the emergence of suicidality in certain patients during the earlyphases of treatment. Pooled analyses of short-term placebo-controlled studies ofantidepressant drugs (SSRIs and others) showed that these drugs increase the risk ofsuicidal thinking and behavior (suicidality) in children, adolescents, and young adults(ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did notshow an increase in the risk of suicidality with antidepressants compared to placebo inadults beyond age 24; there was a reduction with antidepressants compared to placeboin adults aged 65 and older.

The pooled analyses of placebo-controlled studies in children and adolescents with MDD,Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled

analyses of placebo-controlled studies in adults with MDD or other psychiatric disordersincluded a total of 295 short-term studies (median duration of 2 months) of 11antidepressant drugs in over 77,000 patients. There was considerable variation in risk ofsuicidality among drugs, but a tendency toward an increase in the younger patients foralmost all drugs studied. There were differences in absolute risk of suicidality across thedifferent indications, with the highest incidence in MDD. The risk differences (drugversus placebo), however, were relatively stable within age strata and across indications.These risk differences (drug-placebo difference in the number of cases of suicidality per1,000 patients treated) are provided in Table 1.

Table 1: Difference in the Number of Cases of Suicidality per 1,000 PatientsTreated versus Placebo

Age Range Increases Compared to Placebo < 18 14 additional cases

18 to 24 5 additional cases Decreases Compared to Placebo

25 to 64 1 fewer case ≥ 65 6 fewer cases

No suicides occurred in any of the pediatric studies. There were suicides in the adultstudies, but the number was not sufficient to reach any conclusion about drug effect onsuicide.

It is unknown whether the suicidality risk extends to longer term use, i.e., beyondseveral months. However, there is substantial evidence from placebo-controlledmaintenance studies in adults with depression that the use of antidepressants can delaythe recurrence of depression.

All patients being treated with antidepressants for any indication should be monitoredappropriately and observed closely for clinical worsening, suicidality, and unusualchanges in behavior, especially during the initial few months of a course of drug therapy,or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, andmania, have been reported in adult and pediatric patients being treated withantidepressants for MDD, as well as for other indications, both psychiatric andnonpsychiatric. Although a causal link between the emergence of such symptoms andeither the worsening of depression and/or the emergence of suicidal impulses has notbeen established, there is concern that such symptoms may represent precursors toemerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possiblydiscontinuing the medication, in patients whose depression is persistently worse, or whoare experiencing emergent suicidality or symptoms that might be precursors toworsening depression or suicidality, especially if these symptoms are severe, abrupt in

onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered,as rapidly as is feasible, but with recognition that abrupt discontinuation can beassociated with certain symptoms [see Warnings and Precautions (5.7) and Dosage andAdministration (2.8)].

Families and caregivers of patients being treated with antidepressants for MDD or otherindications, both psychiatric and nonpsychiatric, should be alerted about the need tomonitor patients for the emergence of agitation, irritability, unusual changes in behavior,and the other symptoms described above, as well as the emergence of suicidality, andto report such symptoms immediately to healthcare providers. Such monitoring shouldinclude daily observation by families and caregivers. Prescriptions for venlafaxinehydrochloride extended-release capsules should be written for the smallest quantity ofcapsules consistent with good patient management, in order to reduce the risk ofoverdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It isgenerally believed (though not established in controlled studies) that treating such anepisode with an antidepressant alone may increase the likelihood of precipitation of amixed/manic episode in patients at risk for bipolar disorder. Whether any of thesymptoms described above represent such a conversion is unknown. However, prior toinitiating treatment with an antidepressant, patients with depressive symptoms shouldbe adequately screened to determine if they are at risk for bipolar disorder; suchscreening should include a detailed psychiatric history, including a family history ofsuicide, bipolar disorder, and depression. It should be noted that venlafaxinehydrochloride extended-release capsules are not approved for use in treating bipolardepression.

5.2 Serotonin SyndromeThe development of a potentially life-threatening serotonin syndrome has been reportedwith Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, includingvenlafaxine hydrochloride extended-release capsules alone, but particularly withconcomitant use of other serotonergic drugs (including triptans, tricyclicantidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, andSt. John’s wort) and with drugs that impair metabolism of serotonin in particular, MAOIs,both those intended to treat psychiatric disorders and others, such as linezolid orintravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation,hallucinations, delirium, coma) autonomic instability (e.g., tachycardia, labile bloodpressure, hyperthermia, diaphoresis, flushing, and dizziness), neuromuscular symptoms(e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination); seizures andgastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should bemonitored for the emergence of serotonin syndrome.

The concomitant use of venlafaxine hydrochloride extended-release capsules withMAOIs (intended to treat psychiatric disorders) is contraindicated. Venlafaxinehydrochloride extended-release capsules should also not be started in a patient who isbeing treated with MAOIs such as linezolid or intravenous methylene blue. All reportswith methylene blue that provided information on the route of administration involvedintravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involvedthe administration of methylene blue by other routes (such as oral tablets or local tissueinjection) or at lower doses. There may be circumstances when it is necessary to initiatetreatment with a MAOI such as linezolid or intravenous methylene blue in a patient takingvenlafaxine hydrochloride extended-release capsules. Venlafaxine hydrochlorideextended-release capsules should be discontinued before initiating treatment with theMAOI [see Contraindications (4.2), Dosage and Administration (2.6), and DrugInteractions (7.3)].

If concomitant use of venlafaxine hydrochloride extended-release capsules with otherserotonergic drugs (e.g., triptans, tricyclic antidepressants, mirtazapine, fentanyl,lithium, tramadol, buspirone, amphetamines, tryptophan, or St. John's wort) is clinicallywarranted, careful observation of the patient is advised, particularly during treatmentinitiation and dose increases [see Drug Interactions (7.3)]. Patients should be madeaware of the potential risk of serotonin syndrome. Treatment with venlafaxinehydrochloride extended-release capsules and any concomitant serotonergic agentsshould be discontinued immediately if the above events occur, and supportivesymptomatic treatment should be initiated.

5.3 Elevations in Blood PressureIn controlled trials, there were dose-related increases in systolic and diastolic bloodpressure, as well as cases of sustained hypertension [see Adverse Reactions (6.2)].

Monitor blood pressure before initiating treatment with venlafaxine hydrochlorideextended-release capsules and regularly during treatment. Control pre-existinghypertension before initiating treatment with venlafaxine hydrochloride extended-releasecapsules. Use caution in treating patients with pre-existing hypertension orcardiovascular or cerebrovascular conditions that might be compromised by increasesin blood pressure. Sustained blood pressure elevation can lead to adverse outcomes.Cases of elevated blood pressure requiring immediate treatment have been reportedwith venlafaxine hydrochloride extended-release capsules. Consider dose reduction ordiscontinuation of treatment for patients who experience a sustained increase in bloodpressure.

Across all clinical studies with venlafaxine hydrochloride, 1.4% of patients in thevenlafaxine hydrochloride extended-release capsules treated groups experienced a ≥15mm Hg increase in supine diastolic blood pressure (SDBP) ≥ 105 mm Hg, compared to0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxinehydrochloride extended-release capsules treated groups experienced a ≥ 20 mm Hgincrease in supine systolic blood pressure (SSBP) with blood pressure ≥ 180 mm Hg,compared to 0.3% of patients in the placebo groups [see Table 10 in Adverse Reactions

(6.2)]. Venlafaxine hydrochloride extended-release capsules treatment was associatedwith sustained hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits [see Table 11 inAdverse Reactions (6.2)]. An insufficient number of patients received mean doses ofvenlafaxine hydrochloride extended-release capsules over 300 mg per day in clinicalstudies to fully evaluate the incidence of sustained increases in blood pressure at thesehigher doses.

5.4 Abnormal BleedingSSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules, mayincrease the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis,petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitantuse of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Casereports and epidemiological studies (case-control and cohort design) havedemonstrated an association between use of drugs that interfere with serotoninreuptake and the occurrence of gastrointestinal bleeding. Caution patients about the riskof bleeding associated with the concomitant use of venlafaxine hydrochloride extended-release capsules and NSAIDs, aspirin, or other drugs that affect coagulation.

5.5 Angle-Closure GlaucomaThe pupillary dilation that occurs following use of many antidepressant drugs includingvenlafaxine hydrochloride extended-release capsules may trigger an angle closure attackin a patient with anatomically narrow angles who does not have a patent iridectomy.

5.6 Activation of Mania/HypomaniaMania or hypomania was reported in venlafaxine hydrochloride extended-releasecapsules treated patients in the premarketing studies in MDD, SAD, and PD (see Table2). Mania/hypomania has also been reported in a small proportion of patients with mooddisorders who were treated with other marketed drugs to treat MDD. Venlafaxinehydrochloride extended-release capsules should be used cautiously in patients with ahistory of mania or hypomania.

Table 2: Incidence (%) of Mania or Hypomania Reported in VenlafaxineHydrochloride Extended-Release Capsules Treated Patients in the

Premarketing Studies

Indication Venlafaxine

HydrochlorideExtended-Release

Capsules Placebo

MDD 0.3 0GAD 0 0.2SAD 0.2 0PD 0.1 0

5.7 Discontinuation SyndromeDiscontinuation symptoms have been systematically evaluated in patients takingvenlafaxine, including prospective analyses of clinical studies in GAD and retrospectivesurveys of studies in MDD and SAD. Abrupt discontinuation or dose reduction ofvenlafaxine at various doses has been found to be associated with the appearance ofnew symptoms, the frequency of which increased with increased dose level and withlonger duration of treatment. Reported symptoms include agitation, anorexia, anxiety,confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoricmood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia,nausea, nervousness, nightmares, sensory disturbances (including shock-like electricalsensations), somnolence, sweating, tremor, vertigo, and vomiting.

There have been postmarketing reports of serious discontinuation symptoms which canbe protracted and severe. Completed suicide, suicidal thoughts, aggression and violentbehavior have been observed in patients during reduction in venlafaxine hydrochlorideextended-release capsules dosage, including during discontinuation. Otherpostmarketing reports describe visual changes (such as blurred vision or troublefocusing) and increased blood pressure after stopping or reducing the dose ofvenlafaxine hydrochloride extended-release capsules.

During marketing of venlafaxine hydrochloride extended-release capsules, other SNRIs,and SSRIs, there have been spontaneous reports of other adverse events occurringupon discontinuation of these drugs, particularly when abrupt, including the following:irritability, lethargy, emotional lability, tinnitus, and seizures.Patients should be monitored for these symptoms when discontinuing treatment withvenlafaxine hydrochloride extended-release capsules. A gradual reduction in the dose,rather than abrupt cessation, is recommended. If intolerable symptoms occur followinga decrease in the dose or upon discontinuation of treatment, then resuming thepreviously prescribed dose may be considered. Subsequently, the healthcare providermay continue decreasing the dose, but at a more gradual rate. In some patients,discontinuation may need to occur over a period of several months [see Dosage andAdministration (2.8)].

5.8 SeizuresSeizures have occurred with venlafaxine therapy. Venlafaxine hydrochloride extended-release capsules, like many antidepressants, should be used cautiously in patients with ahistory of seizures and should be discontinued in any patient who develops seizures.[Must mitigate the risk: Risk factors, concomitant meds that lower the seizurethreshold.]

5.9 HyponatremiaHyponatremia can occur as a result of treatment with SSRIs and SNRIs, includingvenlafaxine hydrochloride extended-release capsules. In many cases, the hyponatremiaappears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH)secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderlypatients may be at greater risk of developing hyponatremia with SSRIs and SNRIs [see

Use in Specific Populations (8.5)]. Also, patients taking diuretics, or those who areotherwise volume-depleted, may be at greater risk. Consider discontinuation ofvenlafaxine hydrochloride extended-release capsules in patients with symptomatichyponatremia, and institute appropriate medical intervention.

Signs and symptoms of hyponatremia include headache, difficulty concentrating,memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.Signs and symptoms associated with more severe and/or acute cases have includedhallucination, syncope, seizure, coma, respiratory arrest, and death.

5.10 Weight and Height Changes in Pediatric PatientsWeight Changes The average change in body weight and incidence of weight loss (percentage of patientswho lost 3.5% or more) in the placebo-controlled pediatric studies in MDD, GAD, andSAD are shown in Tables 3 and 4.

Table 3: Average Change in Body Weight (kg) From Beginning of Treatment inPediatric Patients in Double-blind, Placebo-controlled Studies of Venlafaxine

Hydrochloride Extended-Release Capsules

Indication (Duration)

Venlafaxine HydrochlorideExtended-Release

Capsules Placebo

MDD and GAD (4 pooled studies, 8 weeks) -0.45 (n = 333) +0.77 (n = 333)

SAD (16 weeks) -0.75 (n = 137) +0.76 (n = 148)

Table 4: Incidence (%) of Pediatric Patients Experiencing Weight Loss (3.5%or more) in Double-blind, Placebo-controlled Studies of Venlafaxine

Hydrochloride Extended-Release Capsules

p < 0.001 versus placebo

Indication (Duration)

Venlafaxine HydrochlorideExtended-Release

Capsules Placebo

MDD and GAD (4 pooled studies, 8 weeks) 18 (n = 333) 3.6 (n = 333)

SAD (16 weeks) 47 (n = 137) 14 (n = 148)

Weight loss was not limited to patients with treatment-emergent anorexia [see Warningsand Precautions (5.11)].

The risks associated with longer term venlafaxine hydrochloride extended-releasecapsules use were assessed in an open-label MDD study of children and adolescents

a

a

a

who received venlafaxine hydrochloride extended-release capsules for up to six months.The children and adolescents in the study had increases in weight that were less thanexpected, based on data from age- and sex-matched peers. The difference betweenobserved weight gain and expected weight gain was larger for children (< 12 years old)than for adolescents (≥ 12 years old).

Height Changes

Table 5 shows the average height increase in pediatric patients in the short-term,placebo-controlled MDD, GAD, and SAD studies. The differences in height increases inGAD and MDD studies were most notable in patients younger than twelve.

Table 5: Average Height Increases (cm) in Pediatric Patients in Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules

p = 0.041

Indication (Duration)

Venlafaxine HydrochlorideExtended-Release

Capsules Placebo

MDD (8 weeks) 0.8 (n = 146) 0.7 (n = 147) GAD (8 weeks) 0.3 (n = 122) 1 (n = 132)SAD (16 weeks) 1 (n = 109) 1 (n = 112)

In the six-month, open-label MDD study, children and adolescents had height increasesthat were less than expected, based on data from age- and sex-matched peers. Thedifference between observed and expected growth rates was larger for children (< 12years old) than for adolescents (≥ 12 years old).

5.11 Appetite Changes in Pediatric PatientsDecreased appetite (reported as treatment-emergent anorexia) was more commonlyobserved in venlafaxine hydrochloride extended-release capsules treated patientsversus placebo-treated patients in the premarketing evaluation of venlafaxinehydrochloride extended-release capsules for MDD, GAD, and SAD (see Table 6).

Table 6: Incidence (%) of Decreased Appetite and Associated DiscontinuationRates (%) in Pediatric Patients in Placebo-controlled Studies of Venlafaxine

Hydrochloride Extended-Release Capsules

The discontinuation rates for weight loss were 0.7% for patients receiving eithervenlafaxine hydrochloride extended-release capsules or placebo.

Indication(Duration)

VenlafaxineHydrochloride

Extended-ReleaseCapsules Incidence

Discontinuation PlaceboIncidenceDiscontinuation

MDD and GAD (pooled, 8 weeks) 10 0 3 -SAD (16 weeks) 22 0.7 3 0

a

a

a

a

5.12 Interstitial Lung Disease and Eosinophilic PneumoniaInterstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapyhave been rarely reported. The possibility of these adverse events should be consideredin venlafaxine-treated patients who present with progressive dyspnea, cough or chestdiscomfort. Such patients should undergo a prompt medical evaluation, anddiscontinuation of venlafaxine therapy should be considered.

5.13 Sexual DysfunctionUse of SNRIs, including venlafaxine hydrochloride extended-release capsules, maycause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients,SNRI use may result in ejaculatory delay or failure, decreased libido, and erectiledysfunction. In female patients, SNRI use may result in decreased libido and delayed orabsent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation ofvenlafaxine hydrochloride extended-release capsules and to inquire specifically aboutchanges in sexual function during treatment, because sexual function may not bespontaneously reported. When evaluating changes in sexual function, obtaining adetailed history (including timing of symptom onset) is important because sexualsymptoms may have other causes, including the underlying psychiatric disorder.Discuss potential management strategies to support patients in making informeddecisions about treatment.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of thelabel:

Hypersensitivity [see Contraindications (4.1)]Suicidal Thoughts and Behaviors in Children, Adolescents, and Adults [see Warningsand Precautions (5.1)]Serotonin Syndrome [see Warnings and Precautions (5.2)]Elevations in Blood Pressure [see Warnings and Precautions (5.3)]Abnormal Bleeding [see Warnings and Precautions (5.4)]Angle Closure Glaucoma [see Warnings and Precautions (5.5)]Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]Discontinuation Syndrome [see Warnings and Precautions (5.7)] Seizure [see Warnings and Precautions (5.8)]Hyponatremia [see Warnings and Precautions (5.9)]Weight and Height changes in Pediatric Patients [see Warnings and Precautions(5.10)]Appetite Changes in Pediatric Patients [see Warnings and Precautions (5.11)]Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions(5.12)]Sexual Dysfunction [see Warnings and Precautions (5.13)]

6.1 Clinical Studies ExperienceBecause clinical studies are conducted under widely varying conditions, adverse reactionrates observed in the clinical studies of a drug cannot be directly compared to rates inthe clinical studies of another drug and may not reflect the rates observed in practice.

Most Common Adverse Reactions

The most commonly observed adverse reactions in the clinical study database invenlafaxine hydrochloride extended-release capsules treated patients in MDD, GAD,SAD, and PD (incidence ≥ 5% and at least twice the rate of placebo) were: nausea(30%), somnolence (15.3%), dry mouth (14.8%), sweating (11.4%), abnormalejaculation (9.9%), anorexia (9.8%), constipation (9.3%), impotence (5.3%) anddecreased libido (5.1%).

Adverse Reactions Reported as Reasons for Discontinuation of Treatment

Combined across short-term, placebo-controlled premarketing studies for all indications,12% of the 3,558 patients who received venlafaxine hydrochloride extended-releasecapsules (37.5 to 225 mg) discontinued treatment due to an adverse experience,compared with 4% of the 2,197 placebo-treated patients in those studies.

The most common adverse reactions leading to discontinuation in ≥ 1% of thevenlafaxine hydrochloride extended-release capsules treated patients in the short-termstudies (up to 12 weeks) across indications are shown in Table 7.

Table 7: Incidence (%) of Patients Reporting Adverse Reactions Leading toDiscontinuation in Placebo-controlled Clinical Studies (up to 12 Weeks

Duration)

Body SystemAdverse Reaction

Venlafaxine HydrochlorideExtended-Release

Capsules n = 3,558

Placebo n = 2,197

Body as a whole Asthenia 1.7 0.5 Headache 1.5 0.8Digestive system Nausea 4.3 0.4Nervous system Dizziness 2.2 0.8 Insomnia 2.1 0.6 Somnolence 1.7 0.3Skin and appendages 1.5 0.6 Sweating 1 0.2

Common Adverse Reactions in Placebo-controlled Studies

The number of patients receiving multiple doses of venlafaxine hydrochloride extended-release capsules during the premarketing assessment for each approved indication isshown in Table 8. The conditions and duration of exposure to venlafaxine in alldevelopment programs varied greatly, and included (in overlapping categories) open anddouble-blind studies, uncontrolled and controlled studies, inpatient (venlafaxinehydrochloride only) and outpatient studies, fixed-dose, and titration studies.

Table 8: Patients Receiving Venlafaxine Hydrochloride Extended-ReleaseCapsules in Premarketing Clinical Studies

In addition, in the premarketing assessment of venlafaxine hydrochloride, multipledoses were administered to 2,897 patients in studies for MDD.

Indication Venlafaxine Hydrochloride Extended-Release Capsules

MDD 705 GAD 1,381SAD 819PD 1,314

The incidences of common adverse reactions (those that occurred in ≥ 2% ofvenlafaxine hydrochloride extended-release capsules treated patients [357 MDDpatients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and morefrequently than placebo) in venlafaxine hydrochloride extended-release capsules treatedpatients in short-term, placebo-controlled, fixed- and flexible-dose clinical studies (doses37.5 to 225 mg per day) are shown in Table 9.

The adverse reaction profile did not differ substantially between the different patientpopulations.

Table 9: Common Adverse Reactions: Percentage of Patients ReportingAdverse Reactions (≥ 2% and > placebo) in Placebo-controlled Studies (up to

12 Weeks Duration) across All Indications

Body System Adverse Reaction

Venlafaxine HydrochlorideExtended-Release Capsules

n = 3,558 Placebo

n = 2,197 Body as a whole Asthenia 12.6 7.8Cardiovascular system Hypertension 3.4 2.6 Palpitation 2.2 2 Vasodilatation 3.7 1.9Digestive system Anorexia 9.8 2.6 Constipation 9.3 3.4 Diarrhea 7.7 7.2 Dry mouth 14.8 5.3 Nausea 30 11.8 Vomiting 4.3 2.7

a

a

Percentages based on the number of men (venlafaxine hydrochloride extended-releasecapsules, n = 1,440; placebo, n = 923) Percentages based on the number of women (venlafaxine hydrochloride extended-release capsules, n = 2,118; placebo, n = 1,274)

Nervous system Abnormal dreams 2.9 1.4 Dizziness 15.8 9.5 Insomnia 17.8 9.5 Libido decreased 5.1 1.6 Nervousness 7.1 5 Paresthesia 2.4 1.4 Somnolence 15.3 7.5 Tremor 4.7 1.6Respiratory system Yawn 3.7 0.2Skin and appendages Sweating (including night sweats) 11.4 2.9Special senses Abnormal vision 4.2 1.6Urogenital system Abnormal ejaculation/orgasm (men) 9.9 0.5 Anorgasmia (men) 3.6 0.1 Anorgasmia (women) 2 0.2 Impotence (men) 5.3 1

Other Adverse Reactions Observed in Clinical Studies

Body as a whole – Photosensitivity reaction, chillsCardiovascular system – Postural hypotension, syncope, hypotension, tachycardiaDigestive system – Gastrointestinal hemorrhage [see Warnings and Precautions(5.4)], bruxismHemic/Lymphatic system – Ecchymosis [see Warnings and Precautions (5.4)]

Metabolic/Nutritional – Hypercholesterolemia, weight gain [see Warnings andPrecautions (5.10)], weight loss [see Warnings and Precautions (5.10)]

Nervous system – Seizures [see Warnings and Precautions (5.8)], manic reaction [seeWarnings and Precautions (5.6)], agitation, confusion, akathisia, hallucinations,hypertonia, myoclonus, depersonalization, apathySkin and appendages – Urticaria, pruritus, rash, alopeciaSpecial senses – Mydriasis, abnormality of accommodation, tinnitus, taste perversionUrogenital system – Urinary retention, urination impaired, urinary incontinence,urinary frequency increased, menstrual disorders associated with increased bleeding orincreased irregular bleeding (e.g., menorrhagia, metrorrhagia)

6.2 Vital Sign Changes

a

b

aa

ba

In placebo-controlled premarketing studies, there were increases in mean bloodpressure (see Table 10). Across most indications, a dose-related increase in meansupine systolic and diastolic blood pressure was evident in patients treated withvenlafaxine hydrochloride extended-release capsules. Across all clinical studies in MDD,GAD, SAD and PD, 1.4% of patients in the venlafaxine hydrochloride extended-releasecapsules groups experienced an increase in SDBP of ≥15 mm Hg along with a bloodpressure ≥ 105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly,1% of patients in the venlafaxine hydrochloride extended-release capsules groupsexperienced an increase in SSBP of ≥ 20 mm Hg with a blood pressure ≥ 180 mm Hg,compared to 0.3% of patients in the placebo groups.

Table 10: Final On-therapy Mean Changes From Baseline in Supine Systolic(SSBP) and Diastolic (SDBP) Blood Pressure (mm Hg) in Placebo-controlled

Studies

Indication (Duration)

Venlafaxine HydrochlorideExtended-Release Capsules Placebo ≤ 75 mg per

day > 75 mg per

day SSBP SDBP SSBP SDBP SSBP SDBP

MDD (8 to 12 weeks) -0.28 0.37 2.93 3.56 -1.08 -0.1GAD (8weeks) -0.28 0.02 2.4 1.68 -1.26 -0.92 (6months) 1.27 -0.69 2.06 1.28 -1.29 -0.74 SAD (12 weeks) -0.29 -1.26 1.18 1.34 -1.96 -1.22 (6 months) -0.98 -0.49 2.51 1.96 -1.84 -0.65PD (10 to 12 weeks) -1.15 0.97 -0.36 0.16 -1.29 -0.99

Venlafaxine hydrochloride extended-release capsules treatment were associated withsustained hypertension (defined as treatment-emergent Supine Diastolic Blood Pressure[SDBP] ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for three consecutive on-therapyvisits (see Table 11). An insufficient number of patients received mean doses ofvenlafaxine hydrochloride extended-release capsules over 300 mg per day in clinicalstudies to fully evaluate the incidence of sustained increases in blood pressure at thesehigher doses.

Table 11: Sustained Elevations in SDBP in Venlafaxine HydrochlorideExtended-Release Capsules Premarketing Studies

Indication Dose Range (mg per day) Incidence (%) MDD 75 to 375 19/705 (3)GAD 37.5 to 225 5/1011 (0.5)

SAD 75 to 225 5/771 (0.6)PD 75 to 225 9/973 (0.9)

Venlafaxine hydrochloride extended-release capsules were associated with meanincreases in pulse rate compared with placebo in premarketing placebo-controlledstudies (see Table 12) [see Warnings and Precautions (5.3, 5.4)].

Table 12: Approximate Mean Final On-therapy Increase in Pulse Rate(beats/min) in Venlafaxine Hydrochloride Extended-Release CapsulesPremarketing Placebo-controlled Studies (up to 12 Weeks Duration)

Indication (Duration)

Venlafaxine HydrochlorideExtended-Release

Capsules

Placebo

MDD (12 weeks) 2 1GAD (8 weeks) 2 <1 SAD (12 weeks) 3 1PD (12 weeks) 1 <1

6.3 Laboratory ChangesSerum Cholesterol

Venlafaxine hydrochloride extended-release capsule was associated with mean finalincreases in serum cholesterol concentrations compared with mean final decreases forplacebo in premarketing MDD, GAD, SAD and PD clinical studies (Table 13).

Table 13: Mean Final On-therapy Changes in Cholesterol Concentrations(mg/dL) in Venlafaxine Hydrochloride Extended-Release Capsules

Premarketing Studies

Indication (Duration)

VenlafaxineHydrochloride Extended-

Release Capsules Placebo

MDD(12 weeks) +1.5 -7.4GAD(8 weeks)(6 months)

+1

+2.3

-4.9-7.7

SAD(12 weeks)(6 months)

+7.9+5.6

-2.9-4.2

PD(12 weeks) 5.8 -3.7

Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in

premarketing placebo-controlled trials for major depressive disorder was associated witha mean final on-therapy increase in serum cholesterol concentration of approximately1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxinehydrochloride extended-release capsules treatment for up to 8 weeks and up to 6months in premarketing placebo-controlled GAD trials was associated with mean finalon-therapy increases in serum cholesterol concentration of approximately 1 mg/dL and2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9mg/dL and 7.7 mg/dL, respectively. Venlafaxine hydrochloride extended-releasecapsules treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapyincreases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL,respectively, for placebo. Venlafaxine hydrochloride extended-release capsulestreatment for up to 12 weeks in premarketing placebo-controlled panic disorder trialswas associated with mean final on-therapy increases in serum cholesterol concentrationof approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL forplacebo.

Patients treated with venlafaxine hydrochloride (immediate release) for at least 3 monthsin placebo-controlled 12-month extension trials had a mean final on-therapy increase intotal cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period andtended to be greater with higher doses. Clinically relevant increases in serum cholesterol,defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baselineand to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% ofvenlafaxine-treated patients and 0% of placebo-treated patients.

Serum Triglycerides

Venlafaxine hydrochloride extended-release capsule was associated with mean final on-therapy increases in fasting serum triglycerides compared with placebo in premarketingclinical studies of SAD and PD up to 12 weeks (pooled data) and 6 months duration(Table 14).

Table 14: Mean Final On-therapy Increases in Triglyceride Concentrations(mg/dL) in Venlafaxine Hydrochloride Extended-Release Capsules

Premarketing StudiesIndication (Duration)

Venlafaxine HydrochlorideExtended-Release Capsules Placebo

SAD(12 weeks) 8.2 0.4SAD(6 months) 11.8 1.8PD(12 weeks) 5.9 0.9PD(6 months) 9.3 0.3

(6 months)

6.4 Pediatric PatientsIn general, the adverse reaction profile of venlafaxine (in placebo-controlled clinicalstudies) in children and adolescents (ages 6 to 17) was similar to that seen for adults.As with adults, decreased appetite, weight loss, increased blood pressure, and increasedserum cholesterol were observed [see Warnings and Precautions (5.3, 5.10, 5.11) andUse in Specific Populations (8.4)].

In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed.

Particularly, the following adverse reactions were observed in pediatric patients:abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

6.5 Adverse Reactions Identified During Postapproval UseThe following adverse reactions have been identified during postapproval use ofvenlafaxine hydrochloride extended-release capsules. Because these reactions arereported voluntarily from a population of uncertain size, it is not always possible toreliably estimate their frequency or establish a causal relationship to drug exposure:

Body as a whole – Anaphylaxis, angioedemaCardiovascular system – QT prolongation, ventricular fibrillation, ventriculartachycardia (including torsade de pointes), takotsubo cardiomyopathyDigestive system – PancreatitisHemic/Lymphatic system – Mucous membrane bleeding [see Warnings andPrecautions (5.4)], blood dyscrasias (including agranulocytosis, aplastic anemia,neutropenia and pancytopenia), prolonged bleeding time, thrombocytopeniaMetabolic/Nutritional – Hyponatremia [see Warnings and Precautions (5.9)],Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see Warnings andPrecautions (5.9)], abnormal liver function tests, hepatitis, prolactin increasedMusculoskeletal – RhabdomyolysisNervous system – Neuroleptic Malignant Syndrome (NMS) [see Warnings andPrecautions (5.2)], serotonergic syndrome [see Warnings and Precautions (5.2)],delirium, extrapyramidal reactions (including dystonia and dyskinesia), impairedcoordination and balance, tardive dyskinesiaRespiratory system – Dyspnea, interstitial lung disease, pulmonary eosinophilia [seeWarnings and Precautions (5.12)]

Skin and appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis,erythema multiformeSpecial senses – Angle-closure glaucoma [see Warnings and Precautions (5.5)]

7 DRUG INTERACTIONS

7.1 Central Nervous System (CNS)-Active DrugsThe risk of using venlafaxine in combination with other CNS-active drugs has not beensystematically evaluated. Consequently, caution is advised when venlafaxinehydrochloride extended-release capsules are taken in combination with other CNS-activedrugs.

7.2 Monoamine Oxidase InhibitorsAdverse reactions, some of which were serious, have been reported in patients whohave recently been discontinued from an MAOI and started on antidepressants withpharmacological properties similar to venlafaxine hydrochloride extended-releasecapsules (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinuedprior to initiation of an MAOI [see Dosage and Administration (2.9), Contraindications(4.2) and Warnings and Precautions (5.2)].

7.3 Serotonergic DrugsBased on the mechanism of action of venlafaxine hydrochloride extended-releasecapsules and the potential for serotonin syndrome, caution is advised when venlafaxinehydrochloride extended-release capsules are coadministered with other drugs that mayaffect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs,linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St.John’s wort. If concomitant treatment with venlafaxine hydrochloride extended-releasecapsules and these drugs is clinically warranted, careful observation of the patient isadvised, particularly during treatment initiation and dose increases. The concomitant useof venlafaxine hydrochloride extended-release capsules with tryptophansupplements are not recommended [see Dosage and Administration (2.9),Contraindications (4.2), and Warnings and Precautions (5.2)].

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, andWarfarin)Serotonin release by platelets plays an important role in hemostasis. The use ofpsychotropic drugs that interfere with serotonin reuptake is associated with theoccurrence of upper gastrointestinal bleeding and concurrent use of an NSAID or aspirinmay potentiate this risk of bleeding [see Warnings and Precautions (5.4)]. Alteredanticoagulant effects, including increased bleeding, have been reported when SSRIs andSNRIs are coadministered with warfarin. Patients receiving warfarin therapy should becarefully monitored when venlafaxine hydrochloride extended-release capsules areinitiated or discontinued.

7.5 Weight Loss AgentsThe safety and efficacy of venlafaxine therapy in combination with weight loss agents,including phentermine, have not been established. Coadministration of venlafaxinehydrochloride extended-release capsules and weight loss agents are not recommended.Venlafaxine hydrochloride extended-release capsules are not indicated for weight lossalone or in combination with other products.

7.6 Effects of Other Drugs on Venlafaxine Hydrochloride Extended-ReleaseCapsules

Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxineand active metabolite O-desmethylvenlafaxine (ODV).

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; C , peakplasma concentrations; EM’s, extensive metabolizers; PM’s, poor metabolizers

* No dose adjustment on co-administration with CYP2D6 inhibitors (Fig 3 and MetabolismSection 12.3)

7.7 Effects of Venlafaxine Hydrochloride Extended-Release Capsules onOther DrugsFigure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs andtheir active metabolites.

max

Abbreviations: AUC, area under the curve; C , peak plasma concentrations; OH,hydroxyl

* Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and90% CI for C and AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8, 5),respectively.

Note:

*: Administration of venlafaxine in a stable regimen did not exaggerate the psychomotorand psychometric effects induced by ethanol in these same subjects when they werenot receiving venlafaxine.

7.8 Drug-Laboratory Test InteractionsFalse-positive urine immunoassay screening tests for phencyclidine (PCP) andamphetamine have been reported in patients taking venlafaxine. This is due to lack ofspecificity of the screening tests. False positive test results may be expected for several

max

max

days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gaschromatography/mass spectrometry, will distinguish venlafaxine from PCP andamphetamine.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyTeratogenic Effects – Pregnancy Category C

Venlafaxine did not cause malformations in offspring of rats or rabbits given doses upto 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on amg/m basis. However, in rats, there was a decrease in pup weight, an increase instillborn pups, and an increase in pup deaths during the first 5 days of lactation, whendosing began during pregnancy and continued until weaning. The cause of these deathsis not known. These effects occurred at 2.5 times (mg/m ) the maximum human dailydose. The no effect dose for rat pup mortality was 0.25 times the human dose on amg/m basis. In reproductive developmental studies in rats and rabbits with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, evidence ofteratogenicity was not observed at exposure margins of 13 in rats and 0.3 in rabbits.There are no adequate and well-controlled studies in pregnant women. Venlafaxinehydrochloride extended-release capsules should be used during pregnancy only if thepotential benefit justifies the potential risk to the fetus. Because animal reproductionstudies are not always predictive of human response, this drug should be used duringpregnancy only if clearly needed.

Non-teratogenic Effects

Neonates exposed to venlafaxine hydrochloride extended-release capsules, otherSNRIs, or SSRIs, late in the third trimester have developed complications requiringprolonged hospitalization, respiratory support, and tube feeding. Such complications canarise immediately upon delivery. Reported clinical findings have included respiratorydistress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting,hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, andconstant crying. These features are consistent with either a direct toxic effect of SSRIsand SNRIs, or possibly a drug discontinuation syndrome. It should be noted, that insome cases the clinical picture is consistent with serotonin syndrome [see Warnings andPrecautions (5.2) and Drug Interactions (7.3)]. When treating a pregnant woman withvenlafaxine hydrochloride extended-release capsules during the third trimester, thephysician should carefully consider the potential risks and benefits of treatment.

8.2 Labor and DeliveryThe effect of venlafaxine on labor and delivery in humans is unknown.

8.3 Nursing MothersVenlafaxine and ODV have been reported to be excreted in human milk. Because of thepotential for serious adverse reactions in nursing infants from venlafaxine hydrochlorideextended-release capsules, a decision should be made whether to discontinue nursing

2

2

2

or to discontinue the drug, taking into account the importance of the drug to themother.

8.4 Pediatric UseTwo placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with venlafaxinehydrochloride extended-release capsules, and the data were not sufficient to support aclaim for use in pediatric patients.

Anyone considering the use of venlafaxine hydrochloride extended-release capsules in achild or adolescent must balance the potential risks with the clinical need [see BoxedWarning, Warnings and Precautions (5.1, 5.10, 5.11) and Adverse Reactions (6.4)].

Although no studies have been designed to primarily assess venlafaxine hydrochlorideextended-release capsule's impact on the growth, development, and maturation ofchildren and adolescents, the studies that have been done suggest that venlafaxinehydrochloride extended-release capsules may adversely affect weight and height [seeWarnings and Precautions (5.10)]. Should the decision be made to treat a pediatricpatient with venlafaxine hydrochloride extended-release capsules, regular monitoring ofweight and height is recommended during treatment, particularly if treatment is to becontinued long-term [see Warnings and Precautions (5.10, 5.11)]. The safety ofvenlafaxine hydrochloride extended-release capsules treatment for pediatric patientshas not been systematically assessed for chronic treatment longer than six months induration. In the studies conducted in pediatric patients (ages 6 to 17), the occurrence ofblood pressure and cholesterol increases considered to be clinically relevant in pediatricpatients was similar to that observed in adult patients. Consequently, the precautions foradults apply to pediatric patients [see Warnings and Precautions (5.3, 6.3)].

8.5 Geriatric UseThe percentage of patients in clinical studies for venlafaxine hydrochloride extended-release capsules for MDD, GAD, SAD, and PD who were 65 years of age or older areshown in Table 15.

Table 15: Percentage (and Number of Patients Studied) of Patients 65 Yearsof Age and Older by Indication

In addition, in the premarketing assessment of venlafaxine hydrochloride (immediaterelease), 12% (357/2,897) of patients were ≥ 65 years of age.

Indication Venlafaxine Hydrochloride Extended-Release Capsules

MDD 4 (14/357)GAD 6 (77/1,381)SAD 1 (10/819)PD 2 (16/1,001)

No overall differences in effectiveness or safety were observed between geriatricpatients and younger patients, and other reported clinical experience generally has notidentified differences in response between the elderly and younger patients. However,

a

a

greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs,including venlafaxine hydrochloride extended-release capsules, have been associatedwith cases of clinically significant hyponatremia in elderly patients, who may be at greaterrisk for this adverse event [see Warnings and Precautions (5.9)].

The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly[see Clinical Pharmacology (12.3)] (see Figure 3). No dose adjustment is recommendedfor the elderly on the basis of age alone, although other clinical circumstances, some ofwhich may be more common in the elderly, such as renal or hepatic impairment, maywarrant a dose reduction [see Dosage and Administration (2.6)].

8.6 Age and GenderA population pharmacokinetic analysis of 404 venlafaxine hydrochloride-treated patientsfrom two studies involving both twice daily and three times daily regimens showed thatdose-normalized trough plasma levels of either venlafaxine or ODV were unaltered byage or gender differences. Dosage adjustment based on the age or gender of a patientis generally not necessary [see Dosage and Administration (2.6)] (see Table 15).

8.7 Use in Patient SubgroupsFigure 3: Pharmacokinetics of venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) in special populations.

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; C , peakplasma concentrations;*Similar effect is expected with strong CYP2D6 inhibitors

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled SubstanceVenlafaxine hydrochloride extended-release capsule is not a controlled substance.

9.2 AbuseWhile venlafaxine has not been systematically studied in clinical studies for its potentialfor abuse, there was no indication of drug-seeking behavior in the clinical studies.However, it is not possible to predict on the basis of premarketing experience the extentto which a CNS-active drug will be misused, diverted, and/or abused once marketed.

max

Consequently, physicians should carefully evaluate patients for history of drug abuseand follow such patients closely, observing them for signs of misuse or abuse ofvenlafaxine (e.g., development of tolerance, incrementation of dose, drug-seekingbehavior).

9.3 DependenceIn vitro studies revealed that venlafaxine has virtually no affinity for opiate,benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.

Venlafaxine was not found to have any significant CNS stimulant activity in rodents. Inprimate drug discrimination studies, venlafaxine showed no significant stimulant ordepressant abuse liability. Discontinuation effects have been reported in patientsreceiving venlafaxine [see Dosage and Administration (2.8)].

10 OVERDOSAGE

10.1 Human ExperienceDuring the premarketing evaluations of venlafaxine hydrochloride extended-releasecapsules (for MDD, GAD, SAD, and PD) and venlafaxine hydrochloride (for MDD), therewere twenty reports of acute overdosage with venlafaxine hydrochloride (6 and 14reports in venlafaxine hydrochloride extended-release capsules and venlafaxinehydrochloride patients, respectively), either alone or in combination with other drugsand/or alcohol.

Somnolence was the most commonly reported symptom. Among the other reportedsymptoms were paresthesia of all four limbs, moderate dizziness, nausea, numb handsand feet, and hot-cold spells 5 days after the overdose. In most cases, no signs orsymptoms were associated with overdose. The majority of the reports involved ingestionin which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. One patient who ingested 2.75 g ofvenlafaxine was observed to have two generalized convulsions and a prolongation ofQTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia wasreported in two of the other patients.

Actions taken to treat the overdose included no treatment, hospitalization andsymptomatic treatment, and hospitalization plus treatment with activated charcoal. Allpatients recovered.

In postmarketing experience, overdose with venlafaxine has occurred predominantly incombination with alcohol and/or other drugs. The most commonly reported events inoverdosage include tachycardia, changes in level of consciousness (ranging fromsomnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes(e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventriculartachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotoninsyndrome, and death have been reported.

Published retrospective studies report that venlafaxine overdosage may be associatedwith an increased risk of fatal outcomes compared to that observed with SSRI

antidepressant products, but lower than that for tricyclic antidepressants.Epidemiological studies have shown that venlafaxine-treated patients have a higherpreexisting burden of suicide risk factors than SSRI-treated patients. The extent towhich the finding of an increased risk of fatal outcomes can be attributed to the toxicityof venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. Prescriptions for venlafaxine hydrochloride extended-release capsules should be written for the smallest quantity of capsules consistent withgood patient management, in order to reduce the risk of overdose.

10.2 Management of OverdosageConsult a Certified Poison Control Center for up-to-date guidance and advice (1-800-222-1222 or www.poison.org). In case of an overdose, provide supportive care,including close medical supervision and monitoring. Treatment should consist of thosegeneral measures employed in the management of overdosage with any drug. Considerthe possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, andventilation. Monitor cardiac rhythm and vital signs. Provide supportive and symptomaticmeasures.

11 DESCRIPTION

Venlafaxine hydrochloride extended-release capsule USP is an extended-release capsulefor once-a-day oral administration that contains venlafaxine hydrochloride USP, a SNRI.

Venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride or (±)-1-[α-[(dimethylamino)methyl]-pmethoxybenzyl]cyclohexanol hydrochloride and has the molecular formula of C H NO HCl. Itsmolecular weight is 313.86. The structural formula is shown as follows:

Venlafaxine hydrochloride USP is a white or almost white crystalline powder, with asolubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodiumchloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.

17 27 2

Drug release is controlled by diffusion through the coating membrane on the spheroidsand is not pH-dependent. Capsules contain venlafaxine hydrochloride USP equivalent to37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of ethyl cellulose,hypromellose, sugar spheres, and talc. The empty hard gelatin capsule shells containiron oxide red, gelatin, titanium dioxide, and sodium lauryl sulphate. In addition, the 37.5mg empty hard gelatin capsule shells contain iron oxide black. The capsules are printedwith edible ink containing black iron oxide and shellac.

Meets the USP Dissolution Test - 4

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionThe exact mechanism of the antidepressant action of venlafaxine in humans isunknown, but is thought to be related to the potentiation of serotonin andnorepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have demonstrated that venlafaxine and its active metabolite, ODV, arepotent and selective inhibitors of neuronal serotonin and norepinephrine reuptake andweak inhibitors of dopamine reuptake.

12.2 PharmacodynamicsVenlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H -histaminergic, or α -adrenergic receptors in vitro. Pharmacologic activity at thesereceptors is hypothesized to be associated with the various anticholinergic, sedative,and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV donot possess monoamine oxidase (MAO) inhibitory activity.

Cardiac Electrophysiology

The effect of venlafaxine on the QT interval was evaluated in a randomized, double-blind,placebo-and positive-controlled three-period crossover thorough QT study in 54 healthyadult subjects. No significant QT prolongation effect of venlafaxine 450 mg wasdetected.

12.3 PharmacokineticsSteady-state concentrations of venlafaxine and ODV in plasma are attained within 3 daysof oral multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over thedose range of 75 to 450 mg per day. Mean±SD steady-state plasma clearance ofvenlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent eliminationhalf-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume ofdistribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV areminimally bound at therapeutic concentrations to plasma proteins (27% and 30%,respectively).

Absorption and Distribution

11

Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the majoractive metabolite. On the basis of mass balance studies, at least 92% of a single oraldose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine isapproximately 45%.

Administration of venlafaxine hydrochloride extended-release capsules (150 mg oncedaily) generally resulted in lower C and later T values than for venlafaxinehydrochloride (immediate release) administered twice daily (Table 16). When equal dailydoses of venlafaxine were administered as either an immediate-release tablet or theextended-release capsule, the exposure to both venlafaxine and ODV was similar for thetwo treatments, and the fluctuation in plasma concentrations was slightly lower with thevenlafaxine hydrochloride extended-release capsules. Therefore, venlafaxinehydrochloride extended-release capsules provide a slower rate of absorption, but thesame extent of absorption compared with the immediate-release tablet.

Table 16: Comparison of C and T Values for Venlafaxine and ODVFollowing Oral Administration of Venlafaxine Hydrochloride Extended-Release

Capsules and Venlafaxine Hydrochloride (Immediate Release) Venlafaxine ODV

C (ng/mL)

T (h)

C (ng/mL)

T (h)

Venlafaxine HydrochlorideExtended-Release Capsules(150 mg once daily)

150 5.5 260 9

Venlafaxine Hydrochloride (75 mg twice daily) 225 2 290 3

Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time ofadministration (AM versus PM) did not affect the pharmacokinetics of venlafaxine andODV from the 75 mg venlafaxine hydrochloride extended-release capsules.

Venlafaxine is not highly bound to plasma proteins; therefore, administration ofvenlafaxine hydrochloride extended-release capsules to a patient taking another drugthat is highly protein-bound should not cause increased free concentrations of the otherdrug.

Metabolism and Elimination

Following absorption, venlafaxine undergoes extensive presystemic metabolism in theliver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine,and other minor metabolites. In vitro studies indicate that the formation of ODV iscatalyzed by CYP2D6; this has been confirmed in a clinical study showing that patientswith low CYP2D6 levels (poor metabolizers) had increased levels of venlafaxine andreduced levels of ODV compared to people with normal CYP2D6 levels (extensivemetabolizers) [see Use in Specific Populations (8.7)].

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as

max max

max max

max max max max

unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), orother minor inactive metabolites (27%). Renal elimination of venlafaxine and itsmetabolites is thus the primary route of excretion.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis

Tumors were not increased by venlafaxine treatment in mice or rats. Venlafaxine wasgiven by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, whichwas 1.7 times the maximum recommended human dose on a mg/m basis. Venlafaxinewas also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day.In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsywere 1 times (male rats) and 6 times (female rats) the plasma concentrations of patientsreceiving the maximum recommended human dose. Plasma levels of the O-desmethylmetabolite (ODV) were lower in rats than in patients receiving the maximumrecommended dose. O-desmethylvenlafaxine (ODV), the major human metabolite ofvenlafaxine, administered by oral gavage to mice and rats for 2 years did not increasethe incidence of tumors in either study. Mice received ODV at dosages up to 500/300mg/kg/day (dosage lowered after 45 weeks of dosing). The exposure at the 300mg/kg/day dose is 9 times that of a human dose of 225 mg/day. Rats received ODV atdosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The exposure at thehighest dose is approximately 8 (males) or 11 (females) times that of a human dose of225 mg/day.

Mutagenesis

Venlafaxine and the major human metabolite, ODV, were not mutagenic in the Amesreverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRTmammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic orclastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sisterchromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivochromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the invitro Chinese hamster ovary cell chromosomal aberration assay or in the in vivochromosomal aberration assay in rats.

Impairment of Fertility

Reproduction and fertility studies of venlafaxine in rats showed no adverse effects ofvenlafaxine on male or female fertility at oral doses of up to 2 times the maximumrecommended human dose of 225 mg/day on a mg/m basis. However, reduced fertilitywas observed in a study in which male and female rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to andduring mating and gestation. This occurred at an ODV exposure (AUC) approximately 2to 3 times that associated with a human venlafaxine dose of 225 mg/day.

14 CLINICAL STUDIES

2

2

14.1 Major Depressive DisorderThe efficacy of venlafaxine hydrochloride extended-release capsules as a treatment forMajor Depressive Disorder (MDD) was established in two placebo-controlled, short-term(8 weeks for study 1; 12 weeks for study 2), flexible-dose studies, with doses starting at75 mg per day and ranging to 225 mg per day in adult outpatients meeting DSM-III-R orDSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose ofvenlafaxine was 75 mg per day. In both studies, venlafaxine hydrochloride extended-release capsules demonstrated superiority over placebo on the primary efficacymeasure defined as change from baseline in the HAM-D-21 total score to the endpointvisit, venlafaxine hydrochloride extended-release capsules also demonstrated superiorityover placebo on the key secondary efficacy endpoint, the Clinical Global Impressions(CGI) Severity of Illness scale. Examination of gender subsets of the population studieddid not reveal any differential responsiveness on the basis of gender.

A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizingvenlafaxine hydrochloride in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of venlafaxine hydrochloride over placebobased on the HAM-D-21 total score. The mean dose in completers was 350 mg per day(study 3).

In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on venlafaxine hydrochloride extended-release capsules (75, 150,or 225 mg, once daily every morning) were randomized to continuation of their samevenlafaxine hydrochloride extended-release capsules dose or to placebo, for up to 26weeks of observation for relapse. Response during the open-label phase was defined asa CGI Severity of Illness item score of ≤3 and a HAM-D-21 total score of ≤10 at the day56 evaluation. Relapse during the double-blind phase was defined as follows: (1) areappearance of major depressive disorder as defined by DSM-IV criteria and a CGISeverity of Illness item score of ≥4 (moderately ill), (2) 2 consecutive CGI Severity ofIllness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for anypatient who withdrew from the study for any reason. Patients receiving continuedvenlafaxine hydrochloride extended-release capsules treatment experienced statisticallysignificantly lower relapse rates over the subsequent 26 weeks compared with thosereceiving placebo (study 4).

In a second longer term trial, adult outpatients with MDD, recurrent type, who hadresponded (HAM-D-21 total score ≤ 12 at the day 56 evaluation) and continued to beimproved [defined as the following criteria being met for days 56 through 180: (1) noHAM-D-21 total score ≥ 20; (2) no more than 2 HAM-D-21 total scores > 10, and (3) nosingle CGI Severity of Illness item score ≥ 4 (moderately ill)] during an initial 26 weeks oftreatment on venlafaxine hydrochloride [100 to 200 mg per day, on a twice dailyschedule] were randomized to continuation of their same venlafaxine hydrochloridedose or to placebo. The follow-up period to observe patients for relapse, defined as aCGI Severity of Illness item score ≥ 4, was for up to 52 weeks. Patients receivingcontinued venlafaxine hydrochloride treatment experienced statistically significantlylower relapse rates over the subsequent 52 weeks compared with those receivingplacebo (study 5).

Table 17: Major Depressive Disorder Studies:

SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval. Difference (drug minus placebo) in least-squares mean change from baseline

* Doses statistically significantly superior to placebo.

Study number

Treatment Group Primary Efficacy Measure: HAM-D Score

Mean BaselineScore (SD)

LS MeanChange

fromBaseline

PlaceboSubtracted

Difference (95%CI)

Study 1 VenlafaxineHydrochlorideExtended-ReleaseCapsules (75 to225 mg/day)*

24.5 -11.7 -4.45(-6.66,-2.25)

Placebo 23.6 -7.24 -Study 2 Venlafaxine

HydrochlorideExtended-ReleaseCapsules (75 to225 mg/day)*

24.5 -15.11 -6.4(-8.45,-4.34)

Placebo 24.9 -8.71 Study 3 Venlafaxine

Hydrochloride(immediaterelease) (150 to375 mg/day)*

28.2 (0.5) -14.9 -10.2 (-14.4,-6)

Placebo 28.6 (0.6) -4.7 -

14.2 Generalized Anxiety DisorderThe efficacy of venlafaxine hydrochloride extended-release capsules as a treatment forGeneralized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled,fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month, placebo-controlled, fixed-dosestudy (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria forGAD.

In one 8-week study, venlafaxine hydrochloride extended-release capsulesdemonstrated superiority over placebo for the 75, 150, and 225 mg per day doses asmeasured by the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-Aanxiety and tension items, and the Clinical Global Impressions (CGI) scale. However, the75 and 150 mg per day doses were not as consistently effective as the highest dose(study 1). A second 8-week study evaluating doses of 75 and 150 mg per day andplacebo showed that both doses were more effective than placebo on some of thesesame outcomes; however, the 75 mg per day dose was more consistently effective than

a

a

the 150 mg per day dose (study 2). A dose-response relationship for effectiveness inGAD was not clearly established in the 75 to 225 mg per day dose range studied.

Two 6-month studies, one evaluating venlafaxine hydrochloride extended-releasecapsules doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluatingvenlafaxine hydrochloride extended-release capsules doses of 75 to 225 mg per day(study 4), showed that daily doses of 75 mg or higher were more effective than placeboon the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during6 months of treatment. While there was also evidence for superiority over placebo forthe 37.5 mg per day dose, this dose was not as consistently effective as the higherdoses. Examination of gender subsets of the population studied did not reveal any differentialresponsiveness on the basis of gender.

Table 18: Generalized Anxiety Disorder Studies:StudyNumber Treatment Group Primary Efficacy Measure: HAM-A Score

MeanBaseline

Score (SD)

LS MeanChange

fromBaseline

(SE)

PlaceboSubtractedDifference

(95% CI)

Study 1

VenlafaxineHydrochlorideExtended-ReleaseCapsules 75 mg

24.7 -11.1 (0.95) -1.5 (-3.8, 0.8)

VenlafaxineHydrochlorideExtended-ReleaseCapsules 150 mg

24.5

-11.7 (0.87)

-2.2 (-4.5, 0.1)

VenlafaxineHydrochlorideExtended-ReleaseCapsules 225 mg

23.6

-12.1 (0.81)

-2.6 (-4.9, -0.3)

Placebo 24.1 -9.5 (0.85)

Study 2

VenlafaxineHydrochlorideExtended-ReleaseCapsules 75 mg

23.7 -10.6 (0.82) -2.6 (-4.6, -0.5)

VenlafaxineHydrochlorideExtended-ReleaseCapsules 150 mg

23 -9.8 (0.86) -1.7 (-3.8, 0.3)

Placebo 23.7 -8 (0.73) Venlafaxine

a

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidenceinterval. Difference (drug minus placebo) in least-squares mean change from baseline

* Doses statistically significantly superior to placebo.

Study 3

HydrochlorideExtended-ReleaseCapsules 37.5 mg

26.6 (0.4) -13.8 -2.8 (-5.1, -0.6)

VenlafaxineHydrochlorideExtended-ReleaseCapsules 75 mg

26.3 (0.4) -15.5 -4.6 (-6.9, -2.3)

VenlafaxineHydrochlorideExtended-ReleaseCapsules 150 mg

26.3 (0.4) -16.4 -5.5 (-7.8, -3.1)

Placebo 26.7 (0.5) -11 - Study4

VenlafaxineHydrochlorideExtended-ReleaseCapsules 75 to 225mg

25 -13.4 (0.79) -4.7 (-6.6, -2.9)

Placebo 24.9 -8.7 (0.7)

14.3 Social Anxiety Disorder (also known as Social Phobia)The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment forSocial Anxiety Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1 to 4) and onedouble-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study,which included doses in a range of 75 to 225 mg per day in adult outpatients meetingDSM-IV criteria for SAD (study 5).

In these five studies, venlafaxine hydrochloride extended-release capsules werestatistically significantly more effective than placebo on change from baseline toendpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidencefor any greater effectiveness of the 150 to 225 mg per day group compared to the 75mg per day group in the 6-month study.

Examination of subsets of the population studied did not reveal any differentialresponsiveness on the basis of gender. There was insufficient information to determinethe effect of age or race on outcome in these studies.

Table 19: Social Anxiety Disorder StudiesStudy

Number Treatment Group Primary Efficacy Measure: LSAS Score

a

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidenceinterval. Difference (drug minus placebo) in least-squares mean change from baseline

* Doses statistically significantly superior to placebo.

MeanBaseline

Score(SD)

LS Mean Changefrom Baseline (SE)

Placebo Subtracted Difference (95% CI)

Study 1

VenlafaxineHydrochlorideExtended-ReleaseCapsules (75 to 225mg)

91.1 -31 (2.22) -11.2 (-5.3, -17.1)

Placebo 86.7 -19.9 (2.22) -

Study 2

VenlafaxineHydrochlorideExtended-ReleaseCapsules (75 to 225MG)

90.8 -32.8 (2.69) -10.7 (-3.7, -17.6)

Placebo 87.4 -22.1 (2.66) -

Study 3

VenlafaxineHydrochlorideExtended-ReleaseCapsules (75 to 225MG)

83.2 -36 (2.35) -16.9 (-22.6, -11.2)

Placebo 83.6 -19.1 (2.40) -12.7 (-6.5, -19)

Study 4

VenlafaxineHydrochlorideExtended-ReleaseCapsules (75 to 225mg)

86.2 -35 (2.64) -14.6 (-21.8, -7.4)

Placebo 86.1 -22.2 (2.47)

Study 5

VenlafaxineHydrochlorideExtended-ReleaseCapsules 75 mg

91.8 -38.1 (3.16) -14.6 (-21.8, -7.4)

VenlafaxineHydrochlorideExtended-ReleaseCapsules (150 to 225mg)

86.2 -37.6 (3.05) -14.1 (-21.3, -6.9)

Placebo 89.3 -23.5 (3.08)

14.4 Panic DisorderThe efficacy of venlafaxine hydrochloride extended-release capsules as a treatment forPanic Disorder (PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without

a

a

agoraphobia. Patients received fixed doses of 75 or 150 mg per day in one study (study1) and 75 or 225 mg per day in the other study (study 2).

Efficacy was assessed on the basis of outcomes in three variables: (1) percentage ofpatients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale(PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale(PDSS) total score; and (3) percentage of patients rated as responders (much improvedor very much improved) on the Clinical Global Impressions (CGI) Improvement scale. Inthese two studies, venlafaxine hydrochloride extended-release capsules were statisticallysignificantly more effective than placebo (for each fixed dose) on all three endpoints, buta dose-response relationship was not clearly established.

Examination of subsets of the population studied did not reveal any differentialresponsiveness on the basis of gender. There was insufficient information to determinethe effect of age or race on outcome in these studies.

In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD whohad responded during a 12-week open phase with venlafaxine hydrochloride extended-release capsules (75 to 225 mg per day) were randomly assigned to continue the samevenlafaxine hydrochloride extended-release capsules dose (75, 150, or 225 mg) orswitch to placebo for observation for relapse under double-blind conditions. Responseduring the open phase was defined as ≤ 1 full-symptom panic attack per week duringthe last 2 weeks of the open phase and a CGI Improvement score of 1 (very muchimproved) or 2 (much improved). Relapse during the double-blind phase was defined ashaving 2 or more full-symptom panic attacks per week for 2 consecutive weeks orhaving discontinued due to loss of effectiveness as determined by the investigatorsduring the study. Randomized patients were in response status for a mean time of 34days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued venlafaxine hydrochloride extended-releasecapsules experienced a statistically significantly longer time to relapse.

Table 20: Panic Disorder Studies:StudyNumber

TreatmentGroup

Primary Efficacy Measure: Whether Free of Full-symptom Panic Attacks Percent of patientsFree of Fullsymptom panicattack

Adjusted OddsRatio to placebo

Adjusted OddsRatio 95%ConfidenceInterval

Study 1

VenlafaxineHydrochlorideExtended-ReleaseCapsules 75mg

54.1% (85/157) 2. 268 (1.43, 3.59)

VenlafaxineHydrochlorideExtended-Release

61.4% (97/158) 3.035 (1.91, 4.82)

a a

*

Odds ratio (drug to placebo) in terms of probability of free of full-symptom panicattacks based on logistic regression model. 95% CI: 95% confidence interval without adjusting for multiple dose arms. Doses statistically significantly superior to placebo.

ReleaseCapsules 150mg Placebo 34.4% (53/154) -- --

Study 2

VenlafaxineHydrochlorideExtended-ReleaseCapsules 75mg

64.1% (100/156) 2.350 (1.46, 3.78)

VenlafaxineHydrochlorideExtended-ReleaseCapsules 225mg

70% (112/160) 2.890 (1.80, 4.64)

Placebo 46.5% (73/157) -- --

14.5 Pediatric PatientsTwo placebo-controlled studies in 766 pediatric patients with MDD and two placebo-controlled studies in 793 pediatric patients with GAD have been conducted withvenlafaxine hydrochloride extended-release capsules, and the data were not sufficient tosupport a claim for use in pediatric patients.

16 HOW SUPPLIED/STORAGE AND HANDLINGVenlafaxine Hydrochloride Extended-Release Capsules USP, 37.5 mg are whiteto off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘3’) ofopaque grey color cap and opaque peach color body imprinted with “E” on cap and “73”on the body with edible black ink.

Bottles of 30 NDC 52343-131-30Bottles of 90 NDC 52343-131-90Venlafaxine Hydrochloride Extended-Release Capsules USP, 75 mg are white tooff white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘1’) ofopaque peach color cap and opaque peach color body imprinted with “E” on cap and“74” on the body with edible black ink. Bottles of 30 NDC 52343-132-30Bottles of 90 NDC 52343-132-90

a

*

*

*

*

Venlafaxine Hydrochloride Extended-Release Capsules USP, 150 mg are whiteto off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘0’) ofopaque dark orange color cap and opaque dark orange color body imprinted with “E” oncap and “89” on the body with edible black ink.

Bottles of 30 NDC 52343-133-30Bottles of 90 NDC 52343-133-90

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Prescribers or other healthcare professionals should inform patients, their families, andtheir caregivers about the benefits and risks associated with treatment with venlafaxinehydrochloride extended-release capsules and should counsel them in its appropriateuse. A patient Medication Guide about “Antidepressant Medicines, Depression and OtherSerious Mental Illnesses, and Suicidal Thoughts or Actions” is available for venlafaxinehydrochloride extended-release capsules. The prescriber or healthcare professionalshould instruct patients, their families, and their caregivers to read the Medication Guideand should assist them in understanding its contents. Patients should be given theopportunity to discuss the contents of the Medication Guide and to obtain answers toany questions they may have. The complete text of the Medication Guide is reprinted atthe end of this document. Patients should be advised of the following issues and shouldbe asked to alert their prescriber if these occur while taking venlafaxine hydrochlorideextended-release capsules.

Suicidal Thoughts and Behaviors

Advise patients, their families and caregivers to look for the emergence of suicidality,worsening of depression, and other psychiatric symptoms (anxiety, agitation, panicattacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia,psychomotor restlessness, hypomania, mania, other unusual changes in behavior),especially early during treatment and when the dose is adjusted up or down. Suchsymptoms should be reported to the patient's prescriber or health professional,especially if they are severe, abrupt in onset, or were not part of the patient's presentingsymptoms. Symptoms such as these may be associated with an increased risk forsuicidal thinking and behavior and indicate a need for very close monitoring [see BoxedWarning and Warnings and Precautions (5.1)].

Concomitant Medication

Advise patients taking venlafaxine hydrochloride extended-release capsules not to useconcomitantly other products containing venlafaxine or desvenlafaxine. Healthcare

professionals should instruct patients not to take venlafaxine hydrochloride extended-release capsules with an MAOI or within 14 days of stopping an MAOI and to allow 7days after stopping venlafaxine hydrochloride extended-release capsules before startingan MAOI [see Contraindications (4.2)].

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome, with theconcomitant use of venlafaxine hydrochloride extended-release capsules and triptans,tramadol, amphetamines, tryptophan supplements, with antipsychotics or otherdopamine antagonists, or other serotonergic agents [see Warnings and Precautions(5.2) and Drug Interactions (7.3)].

Elevated Blood Pressure

Advise patients that they should have regular monitoring of blood pressure when takingvenlafaxine hydrochloride extended-release capsules [see Warnings and Precautions(5.3)]. Abnormal Bleeding

Patients should be cautioned about the concomitant use of venlafaxine hydrochlorideextended-release capsules and NSAIDs, aspirin, warfarin, or other drugs that affectcoagulation since combined use of psychotropic drugs that interfere with serotoninreuptake and these agents has been associated with an increased risk of bleeding [seeWarnings and Precautions (5.4)].

Angle Closure Glaucoma

Patients should be advised that taking venlafaxine hydrochloride extended-releasecapsules can cause mild pupillary dilation, which in susceptible individuals, can lead to anepisode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angleglaucoma because angle closure glaucoma, when diagnosed, can be treated definitivelywith iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma.Patients may wish to be examined to determine whether they are susceptible to angleclosure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible[see Warnings and Precautions (5.5)].

Activation of Mania/Hypomania

Advise patients, their families and caregivers to observe for signs of activation ofmania/hypomania [see Warnings and Precautions (5.6)].

Cardiovascular/Cerebrovascular Disease

Caution is advised in administering venlafaxine hydrochloride extended-release capsules

to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders [seeAdverse Reactions (6.1)].

Serum Cholesterol and Triglyceride Elevation

Advise patients that elevations in total cholesterol, LDL and triglycerides may occur andthat measurement of serum lipids may be considered [see Warnings and Precautions(6.3)].

Discontinuation Syndrome

Advise patients not to stop taking venlafaxine hydrochloride extended-release capsuleswithout talking first with their healthcare professional. Patients should be aware thatdiscontinuation effects may occur when stopping venlafaxine hydrochloride extended-release capsules [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

Sexual Dysfunction

Advise patients that use of venlafaxine hydrochloride extended-release capsules maycause symptoms of sexual dysfunction in both male and female patients. Informpatients that they should discuss any changes in sexual function and potentialmanagement strategies with their healthcare provider [see Warnings and Precautions(5.13)].

Interference with Cognitive and Motor Performance

Caution patients about operating hazardous machinery, including automobiles, until theyare reasonably certain that venlafaxine hydrochloride extended-release capsules therapydoes not adversely affect their ability to engage in such activities.

Alcohol

Advise patients to avoid alcohol while taking venlafaxine hydrochloride extended-releasecapsules [see Drug Interactions (7.6)].

Allergic Reactions

Advise patients to notify their physician if they develop allergic phenomena such as rash,hives, swelling, or difficulty breathing.

Pregnancy

Advise patients to notify their physician if they become pregnant or intend to becomepregnant during therapy [see Use in Specific Populations (8.1)].

Nursing

Advise patients to notify their physician if they are breast-feeding an infant [see Use inSpecific Populations (8.3)].

Residual Spheroids

Venlafaxine hydrochloride extended-release capsule contains spheroids, which releasethe drug slowly into the digestive tract. The insoluble portion of these spheroids iseliminated, and patients may notice spheroids passing in the stool or via colostomy.Patients should be informed that the active medication has already been absorbed bythe time the patient sees the spheroids.

Dispense with Medication Guide available athttp://www.acetrishealth.com/med-guides.html

Distributed by: Acetris Health, LLCSaddle Brook, NJ 07663

Made in India

Code: TS/DRUGS/19/1993

Revised: 01/2022

Medication GuideVenlafaxine Hydrochloride Extended-Release Capsules USP(ven'' la fax' een hye'' droe klor' ide)Read the Medication Guide that comes with venlafaxine hydrochloride extended-release capsules before you start taking them and each time you get a refill. Theremay be new information. This Medication Guide does not take the place of talking to yourhealthcare provider about your medical condition or treatment. Talk with your healthcareprovider if there is something you do not understand or want to learn more about.What is the most important information I should know about venlafaxinehydrochloride extended-release capsules?Venlafaxine hydrochloride extended-release capsules and other antidepressantmedicines may cause serious side effects, including:

1. Suicidal thoughts or actions:

Venlafaxine hydrochloride extended-release capsules and otherantidepressant medicines may increase suicidal thoughts or actions insome children, teenagers, or young adults within the first few months oftreatment or when the dose is changed.Depression or other serious mental illnesses are the most important causes ofsuicidal thoughts or actions.Watch for these changes and call your healthcare provider right away if you notice:

New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially

if severe.Pay particular attention to such changes when venlafaxine hydrochlorideextended-release capsules are started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you areworried about symptoms.

Call your healthcare provider right away if you have any of the followingsymptoms, or call 911 if an emergency, especially if they are new, worse, orworry you:

attempts to commit suicideacting on dangerous impulsesacting aggressive or violentthoughts about suicide or dyingnew or worse depressionnew or worse anxiety or panic attacksfeeling agitated, restless, angry or irritabletrouble sleepingan increase in activity or talking more than what is normal for youother unusual changes in behavior or moodVisual problems

eye painchanges in visionswelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eyeexamination to see if you are at risk and receive preventative treatment if you are.

Call your healthcare provider right away if you have any of the followingsymptoms, or call 911 if an emergency. Venlafaxine hydrochloride extended-release capsules may be associated with these serious side effects:

2. Serotonin SyndromeThis condition can be life-threatening and may include:

agitation, hallucinations, coma or other changes in mental statuscoordination problems or muscle twitching (overactive reflexes)racing heartbeat, high or low blood pressuresweating or fevernausea, vomiting, or diarrheamuscle rigidity

3. Changes in blood pressure. Venlafaxine hydrochloride extended-releasecapsules may:

increase your blood pressure. Control high blood pressure before starting treatment

and monitor blood pressure regularly

4. Enlarged pupils (mydriasis).

5. Anxiety and insomnia.

6. Changes in appetite or weight.

7. Manic/hypomanic episodes:

greatly increased energysevere trouble sleepingracing thoughtsreckless behaviorunusually grand ideasexcessive happiness or irritabilitytalking more or faster than usual

8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

headacheweakness or feeling unsteadyconfusion, problems concentrating or thinking or memory problems

9. Seizures or convulsions.10. Abnormal bleeding: Venlafaxine hydrochloride extended-release capsulesand other antidepressant medicines may increase your risk of bleeding or bruising,especially if you take the blood thinner warfarin (Coumadin , Jantoven ), a non-steroidalanti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

11. Elevated cholesterol.

12. Lung disease and pneumonia: Venlafaxine hydrochloride extended-releasecapsules may cause rare lung problems. Symptoms include:

worsening shortness of breathcoughchest discomfort

13. Severe allergic reactions:

trouble breathingswelling of the face, tongue, eyes or mouthrash, itchy welts (hives) or blisters, alone or with fever or joint pain.

® ®

14. Sexual Problems (dysfunction). Taking serotonin and norepinephrine reuptakeinhibitors (SNRIs), including venlafaxine hydrochloride extended-releasecapsules, may cause sexual problems.

Symptoms in males may include:Delayed ejaculation or inability to have an ejaculationDecreased sex driveProblems getting or keeping an erection

Symptoms in females may include:Decreased sex driveDelayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or ifyou have any questions or concerns about sexual problems during treatment withvenlafaxine hydrochloride extended-release capsules. There may be treatmentsyour healthcare provider can suggest.

Do not stop venlafaxine hydrochloride extended-release capsules withoutfirst talking to your healthcare provider. Stopping venlafaxine hydrochlorideextended-release capsules too quickly or changing from another antidepressant tooquickly may cause serious symptoms. Symptoms may include the following (some ofwhich can be severe and last for a long time):

anxiety, irritability, aggressiveness, violent behaviorfeeling tired, restless or problems sleepingheadache, sweating, dizzinesselectric shock-like sensations, shaking, confusion, nightmaresvomiting, nausea, diarrheaproblems with eyesight such as blurred vision or trouble focusingincreased blood pressure

What are venlafaxine hydrochloride extended-release capsules?

Venlafaxine hydrochloride extended-release capsules are a prescription medicineused to treat depression. It is important to talk with your healthcare provider about therisks of treating depression and also the risks of not treating it. You should discuss alltreatment choices with your healthcare provider. Venlafaxine hydrochlorideextended-release capsules are also used to treat:

Generalized Anxiety Disorder (GAD)Social Anxiety Disorder (SAD)Panic Disorder (PD)

Talk to your healthcare provider if you do not think that your condition is getting betterwith venlafaxine hydrochloride extended-release capsules treatment.

Who should not take venlafaxine hydrochloride extended-release capsules?Do not take venlafaxine hydrochloride extended-release capsules if you:

are allergic to venlafaxine hydrochloride or any of the ingredients in venlafaxine

hydrochloride extended-release capsules. See the end of this Medication Guidefor a complete list of ingredients in venlafaxine hydrochloride extended-releasecapsules.have uncontrolled angle-closure glaucomatake a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider orpharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.

Do not take an MAOI within 7 days of stopping venlafaxine hydrochlorideextended-release capsules unless directed to do so by your physician.Do not start venlafaxine hydrochloride extended-release capsules if youstopped taking an MAOI in the last 2 weeks unless directed to do so by yourphysician.

People who take venlafaxine hydrochloride extended-release capsules closein time to an MAOI may have serious or even life-threatening side effects.Get medical help right away if you have any of these symptoms:

high feveruncontrolled muscle spasmsstiff musclesrapid changes in heart rate or blood pressureconfusionloss of consciousness (pass out)

What should I tell my healthcare provider before taking venlafaxinehydrochloride extended-release capsules? Ask if you are not sure.

Before starting venlafaxine hydrochloride extended-release capsules, tell yourhealthcare provider if you:

Are taking certain drugs such as:Amphetamines

Medicines used to treat migraine headaches such as:triptans

Medicines used to treat mood, anxiety, psychotic or thought disorders, such as:tricyclic antidepressantslithiumSSRIsSNRIsantipsychotic drugs

Medicines used to treat pain such as:tramadol

Medicines used to thin your blood such as:warfarin

Medicines used to treat heartburn such as:Cimetidine

Over-the-counter medicines or supplements such as:Aspirin or other NSAIDsTryptophanSt. John’s Wort

have heart problems

have diabeteshave liver problemshave kidney problemshave thyroid problemshave or had seizures or convulsionshave bipolar disorder or maniahave low sodium levels in your bloodhave high blood pressurehave high cholesterolhave or had bleeding problemsare pregnant or plan to become pregnant. It is not known if venlafaxinehydrochloride extended-release capsules will harm your unborn baby. Talk toyour healthcare provider about the benefits and risks of treating depression duringpregnancyare breast-feeding or plan to breast-feed. Some venlafaxine hydrochloride maypass into your breast milk. Talk to your healthcare provider about the best way tofeed your baby while taking venlafaxine hydrochloride extended-releasecapsules.

Tell your healthcare provider about all the medicines that you take, includingprescription and non-prescription medicines, vitamins, and herbal supplements.Venlafaxine hydrochloride extended-release capsules and some medicines mayinteract with each other, may not work as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take venlafaxinehydrochloride extended-release capsules with your other medicines. Do not startor stop any medicine while taking venlafaxine hydrochloride extended-releasecapsules without talking to your healthcare provider first.

If you take venlafaxine hydrochloride extended-release capsules, you should nottake any other medicines that contain (venlafaxine) including: venlafaxine hydrochloride.

How should I take venlafaxine hydrochloride extended-release capsules?

Take venlafaxine hydrochloride extended-release capsules exactly asprescribed. Your healthcare provider may need to change the dose of venlafaxinehydrochloride extended-release capsules until it is the right dose for you.Venlafaxine hydrochloride extended-release capsules are to be taken withfood.If you miss a dose of venlafaxine hydrochloride extended-release capsules,take the missed dose as soon as you remember. If it is almost time for the nextdose, skip the missed dose and take your next dose at the regular time. Do not taketwo doses of venlafaxine hydrochloride extended-release capsules at thesame time.If you take too much venlafaxine hydrochloride, call your healthcare provider orpoison control center right away, or get emergency treatment.

When switching from another antidepressant to venlafaxine hydrochlorideextended-release capsules your doctor may want to lower the dose of the initialantidepressant first to avoid side effects.

What should I avoid while taking venlafaxine hydrochloride extended-releasecapsules?Venlafaxine hydrochloride extended-release capsules can cause sleepiness ormay affect your ability to make decisions, think clearly, or react quickly. You should notdrive, operate heavy machinery, or do other dangerous activities until you know howvenlafaxine hydrochloride extended-release capsules affect you. Do not drinkalcohol while using venlafaxine hydrochloride extended-release capsules.

What are the possible side effects of venlafaxine hydrochloride extended-release capsules?Venlafaxine hydrochloride extended-release capsules may cause serious sideeffects, including:

See “What is the most important information I should know about venlafaxinehydrochloride extended-release capsules?”Increased cholesterol- have your cholesterol checked regularlyNewborns whose mothers take venlafaxine hydrochloride extended-releasecapsules in the third trimester may have problems right after birth including:

problems feeding and breathingseizuresshaking, jitteriness or constant crying

Angle-closure glaucoma

Common possible side effects in people who take venlafaxine hydrochlorideextended-release capsules include:

unusual dreamssexual problemsloss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouthfeeling tired, fatigued or overly sleepychange in sleep habits, problems sleepingyawningtremor or shakingdizziness, blurred visionsweatingfeeling anxious, nervous or jitteryheadacheincrease in heart rate

Tell your healthcare provider if you have any side effect that bothers you or that doesnot go away. These are not all the possible side effects of venlafaxine hydrochlorideextended-release capsules. For more information, ask your healthcare provider orpharmacist.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAYREPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.

How should I store venlafaxine hydrochloride extended-release capsules?

Store venlafaxine hydrochloride extended-release capsules at roomtemperature between 20° to 25°C (68° to 77°F). Keep venlafaxine hydrochloride extended-release capsules in a dry place.

Keep venlafaxine hydrochloride extended-release capsules and all medicinesout of the reach of children.General information about venlafaxine hydrochloride extended-releasecapsules

Medicines are sometimes prescribed for purposes other than those listed in a MedicationGuide. Do not use venlafaxine hydrochloride extended-release capsules for acondition for which it was not prescribed. Do not give venlafaxine hydrochlorideextended-release capsules to other people, even if they have the same condition.They may harm them.

This Medication Guide summarizes the most important information about venlafaxinehydrochloride extended-release capsules. If you would like more information, talkwith your healthcare provider. You may ask your healthcare provider or pharmacist forinformation about venlafaxine hydrochloride extended-release capsules that iswritten for healthcare professionals.

For more information about venlafaxine hydrochloride extended-releasecapsules call 1-833-395-6929.

What are the ingredients in venlafaxine hydrochloride extended-releasecapsules?

Active ingredient: Venlafaxine hydrochloride

Inactive ingredients:Extended-Release Capsules: Ethyl cellulose, hypromellose, sugar spheres, and talc.The empty hard gelatin capsule shells contain iron oxide red, gelatin, titanium dioxide,and sodium lauryl sulphate. In addition, the 37.5 mg empty hard gelatin capsule shellscontain iron oxide black. The capsules are printed with edible ink containing black ironoxide and shellac.

This Medication Guide has been approved by the U.S. Food and Drug Administration forall antidepressants.

Coumadin is a registered trademark of Bristol Myers Squibb.®

®

Jantoven is a registered trademark of Upsher-Smith Laboratories Inc.

Dispense with Medication Guide available athttp://www.acetrishealth.com/med-guides.html

Distributed by: Acetris Health, LLCSaddle Brook, NJ 07663

Made in India

Code: TS/DRUGS/19/1993

Revised: 01/2022

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 37.5 mg (30 Capsule Bottle)30 Capsules NDC 52343-131-30

Venlafaxine HydrochlorideExtended-Release Capsules USP37.5 mg*PHARMACIST: Dispense the MedicationGuide provided separately to each patient.

Rx only Acetris

®

TM

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 75 mg (30 Capsule Bottle)30 Capsules NDC 52343-132-30

Venlafaxine HydrochlorideExtended-Release Capsules USP75 mg*PHARMACIST: Dispense the MedicationGuide provided separately to each patient.Rx only Acetris

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL -150 mg (30 Capsule Bottle)30 Capsules NDC 52343-133-30

Venlafaxine HydrochlorideExtended-ReleaseCapsules USP150 mg*PHARMACIST: Dispense the MedicationGuide provided separately to each patient.Rx only Acetris

TM

TM

VENLAFAXINE HYDROCHLORIDE venlafaxine hydrochloride capsule, extended release

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52343-131

Route of Administration ORAL

Active Ingredient/Active MoietyIngredient Name Basis of

Strength Strength

VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE -UNII:GRZ5RCB1QG) VENLAFAXINE 37.5 mg

Inactive IngredientsIngredient Name Strength

ETHYLCELLULOSE (20 MPA.S) (UNII: BJG0S321QY) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) SUCROSE (UNII: C151H8M554) STARCH, CORN (UNII: O8232NY3SJ) TALC (UNII: 7SEV7J4R1U) FERRIC OXIDE RED (UNII: 1K09F3G675) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) SODIUM LAURYL SULFATE (UNII: 368GB5141J) FERROSOFERRIC OXIDE (UNII: XM0M87F357) SHELLAC (UNII: 46N107B71O)

Product Characteristics

Color GRAY (Opaque Grey) , ORANGE (Opaque Peach) Score no scoreShape CAPSULE Size 16mmFlavor Imprint Code E;73Contains

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:52343-131-

3030 in 1 BOTTLE; Type 0: Not a CombinationProduct 06/01/2011

2 NDC:52343-131-90

90 in 1 BOTTLE; Type 0: Not a CombinationProduct 06/01/2011

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

ANDA ANDA200834 06/01/2011

VENLAFAXINE HYDROCHLORIDE venlafaxine hydrochloride capsule, extended release

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52343-132

Route of Administration ORAL

Active Ingredient/Active MoietyIngredient Name Basis of

Strength Strength

VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE -UNII:GRZ5RCB1QG) VENLAFAXINE 75 mg

Inactive IngredientsIngredient Name Strength

ETHYLCELLULOSE (20 MPA.S) (UNII: BJG0S321QY) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) SUCROSE (UNII: C151H8M554) STARCH, CORN (UNII: O8232NY3SJ) TALC (UNII: 7SEV7J4R1U) FERRIC OXIDE RED (UNII: 1K09F3G675) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) SODIUM LAURYL SULFATE (UNII: 368GB5141J) FERROSOFERRIC OXIDE (UNII: XM0M87F357)

SHELLAC (UNII: 46N107B71O)

Product CharacteristicsColor ORANGE (Opaque Peach) Score no scoreShape CAPSULE Size 19mmFlavor Imprint Code E;74Contains

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:52343-132-

3030 in 1 BOTTLE; Type 0: Not a CombinationProduct 06/01/2011

2 NDC:52343-132-90

90 in 1 BOTTLE; Type 0: Not a CombinationProduct 06/01/2011

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

ANDA ANDA200834 06/01/2011

VENLAFAXINE HYDROCHLORIDE venlafaxine hydrochloride capsule, extended release

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52343-133

Route of Administration ORAL

Active Ingredient/Active MoietyIngredient Name Basis of

Strength Strength

VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE -UNII:GRZ5RCB1QG) VENLAFAXINE 150 mg

Inactive IngredientsIngredient Name Strength

ETHYLCELLULOSE (20 MPA.S) (UNII: BJG0S321QY) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) SUCROSE (UNII: C151H8M554) STARCH, CORN (UNII: O8232NY3SJ) TALC (UNII: 7SEV7J4R1U) FERRIC OXIDE RED (UNII: 1K09F3G675)

ACETRIS HEALTH, LLC

GELATIN, UNSPECIFIED (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) SODIUM LAURYL SULFATE (UNII: 368GB5141J) FERROSOFERRIC OXIDE (UNII: XM0M87F357) SHELLAC (UNII: 46N107B71O)

Product CharacteristicsColor ORANGE (Opaque Dark Orange) Score no scoreShape CAPSULE Size 21mmFlavor Imprint Code E;89Contains

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:52343-133-

3030 in 1 BOTTLE; Type 0: Not a CombinationProduct 06/01/2011

2 NDC:52343-133-90

90 in 1 BOTTLE; Type 0: Not a CombinationProduct 06/01/2011

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

ANDA ANDA200834 06/01/2011

Labeler - ACETRIS HEALTH, LLC (080500964)

Registrant - Aurobindo Pharma Limited (650082092)

EstablishmentName Address ID/FEI Business Operations

Aurobindo PharmaLimited 918917642 ANALYSIS(52343-131, 52343-132, 52343-133) , MANUFACTURE(52343-131,

52343-132, 52343-133)

Revised: 3/2022